Novel Lactam Derivatives

ABSTRACT

The invention thus provides compounds of formula (I)  
                 
a salt, or solvate thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of 10/492,062 filed on Apr. 8, 2004which was filed pursuant to 35 U.S.C. § 371 as a United States NationalPhase Application of International Application No. PCT/US02/32740 filedOct. 15, 2002, which claims priority from GB 0124627.1 filed Oct. 15,2001.

FIELD OF THE INVENTION

This invention relates to novel lactam derivatives which are antagonistsat the human 11CBy receptors, to processes for their preparation, topharmaceutical compositions containing them and to their uses intherapy.

WO01/21577 (Takeda) relates to a compound of the formula

wherein Ar¹ is a cyclic group which may have substituents, X is a spacerhaving a main chain of 1 to 6 atoms, Y is a bond or a spacer having amain chain of 1 to 6 atoms, Ar is a monocyclic aromatic ring which maybe condensed with a 4 to 8 membered non-aromatic ring, and may havefurther substituents; R¹ and R² are independently hydrogen or ahydrocarbon group which may have substituents; R¹ and R² together withthe adjacent nitrogen atom may form a nitrogen containing hetero ringwhich may have substituents; R² may form a spiro ring together with Ar;or R² together with the adjacent nitrogen atom may form a nitrogencontaining hetero ring which may have substituents; or a salt thereof,and which compounds are antagonists of a melanin concentrating hormone.Such compounds are suggested as being useful for preventing or treatingobesity.

We have now found a novel group of compounds that exhibit a usefulprofile of activity as antagonists of the human 11CBy receptor (alsoreferred to as MCHR1) disclosed in Nature 400, 261-265 (1999).

SUMMARY OF THE INVENTION

The invention thus provides compounds of formula (I)

a salt or solvate thereof, wherein

M is a group selected from the group consisting of O, S, C═O, NH andCH₂;

L is a 2 or 3 membered alkylene chain;

wherein together M-L may be optionally substituted by at least onemoiety selected from the group consisting of methyl, ethyl, hydroxy andC₁₋₃ alkoxy;

R¹ and R² are each independently selected from the group consisting ofhydrogen,

C₁₋₆ straight or branched alkyl which may be optionally substituted byphenyl, and C₃₋₆ cycloalkyl optionally substituted by one or more C₁₋₆alkyl groups;

each R⁶ is the same or different and is independently selected from thegroup consisting of hydroxy, C₁₋₂alkyl, C₁₋₃alkoxy, halo, C₂₋₃alkenyl,benzyl, and —C(R^(a))NOR^(b), wherein R^(a) and R^(b) are eachindependently selected from the group consisting of hydrogen, methyl,methoxymethyl, methoxymethoxyl, and methoxyethoxyl; and n is 1, 2, 3, or4;

QY is a bicyclic fused heterocyclic ring wherein Q and Y are each onering of said bicyclic fused heterocyclic group, wherein said Y ringcontains from 1 to 3 nitrogens and is bound to the phenyl ring offormula (I) via a nitrogen atom, and said Q ring is a 5 or 6 memberedaryl or heterocyclic ring having a group ZR³; Z is bound to the Q ring;

Z is selected from the group consisting of a direct bond, NH, NCH₃, O, Sor CH₂; and

R³ is a group selected from the group consisting of aryl, alk-2-en-1-yl,cycloalkyl and cycloalk-2-en-1-yl and wherein said aryl, alk-2-en-1-yl,cycloalkyl, and cycloalk-2-en-1-yl are optionally substituted from 1 to3 times with a subsittuent selected from the group consisting of C₁₋₃alkyl, halo, amino, alkylamino, dialkylamino, hydroxy, C₁₋₃ alkoxy,cyano, trifluoromethyl, and methylthio groups.

The invention also includes embodiments to (i) a pharmaceuticalformulation comprising a compound of formula (I), (ii) the use of acompound of formula (I) or a pharmaceutical formulation comprising theformula (I) in therapy, and (iii) processes for the preparation of acompound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

In the present invention, unless otherwise stated, references to salts,include both physiologically acceptable salts and non-physiologicallyacceptable salts of compounds of formula (I). The compounds of formula(I) and salts thereof may form solvates (e.g. hydrates) and theinvention includes all such solvates.

As used herein, “a compound of the invention” or a compound of formula(I) means a compound of formula (I) or a pharmaceutically acceptablesalt, or solvate thereof.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s) thatoccur and events that do not occur.

The term “alkyl” as a group or part of a group (e.g., alkoxy,alkylamino, etc.) refers to a straight or branched alkyl group. Saidalkyl contains from 1 to 6 carbon atoms unless otherwise specified.Examples of such C₁₋₆ alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl or hexyl.

The term “alk-2-en-1-yl” refers to a straight or branched C₃₋₆alk-2-en-1-yl group.

The term “cycloalkyl” refers to non-aromatic monocyclic carbocyclicrings having 3 to 7 carbon atoms which may be substituted by a moietyselected from the group consisting of hydroxy, C₁₋₃ alkoxy, and halo.

The term “halo” or “halogen” refers to the elements fluorine, chlorine,bromine, and iodine, unless otherwise specified.

The term “cycloalk-2-en-1-yl” refers to a C₅₋₇ cycloalk-2-en-1-yl group.

The term “aryl” preferably refers to phenyl, but also includes fusedaryl rings such as naphthyl.

The terms “heterocycle” and “heterocyclic” refer to a ring systemcomposed of C and at least one other atom selected from the groupconsisting of N, O, and S. Heterocycles may or may not be heteroaromaticas defined below. In other words, heteroaromatics are heterocycles, butall heterocycles are not heteroaromatic.

The term “heteroaryl” and “heteroaromatic” refer to a monocyclic orbicylic aromatic ring system composed of C and at least one other atomselected from the group consisting of N, O, and S.

The terms “members” (and variants thereof, e.g., “membered”) in thecontext of heterocyclic and heteroaryl groups refers to the total atoms,carbon and heteroatoms (N, O, and/or S) which form the ring. Thus, anexample of a 6-membered heterocyclic ring is piperidine and an exampleof a 6-membered heteroaryl ring is pyridine.

In formula (I), M is selected from the group consisting of O, S, C═O,NH, and CH₂. Preferably M is O or CH₂. Most preferably, M is O.

L of formula (I) is a 2 to 3 membered alkylene chain (that is, (CH₂)₂ or(CH₂)₃). Preferaby, L is (CH₂)₂. When the group L is linked to thephenyl ring of formula (I) via a R⁶ substituent, said R⁶ is located inthe ortho position to the group M. Examples of the resultant bicyclicstructure include 1,4-benzodioxan; benzopyran; 1,2-dihydrobezopyran;1,2,3,4-tetrahydronaphthalene; and 1,2-dihydronaphthalene.

In formula (I), in (i) R¹ and R² are each independently selected fromthe group consisting of hydrogen, C₁₋₆ straight or branched alkyl whichmay be optionally substituted by phenyl, and C₃₋₆ cycloalkyl optionallysubstituted by one to four C₁₋₆ alkyl groups. When R¹ and R²independently represent C₁₋₆ alkyl, then preferred examples of such R¹and R² groups include methyl and isopropyl.

Alternatively, in (ii) R¹ and R² together with the nitrogen atom towhich they are bonded form a 4-8 membered heterocyclic ring or a 7-10membered bicyclic heterocyclic ring (containing 1, 2, or 3 heteroatomsselected from N, O and S), wherein said 4 to 8 membered heterocyclicring and said 7 to 10 membered bicyclic heterocyclic ring are optionallysubstituted with a substituent selected from the group consisting ofphenyl and from one to four C₁₋₃ alkyl.

When R₁ and R₂ together with the nitrogen atom to which they are bondedor attached form a 4-8 membered heterocyclic ring, examples of suchrings include azetendinyl, pyrrolidinyl or piperidinyl, which rings maybe substituted by 1-4 methyl groups or a phenyl group (e.g.pyrrolidinyl, 2-methylpyrrolidinyl, 2,5-dimethylpyrrolidinyl, piperidyl,2-methylpiperidinyl, 2,6-dimethylpiperidinyl, 2,2,6,6,tetramethylpiperidinyl or 4-phenylpiperidinyl).

When R¹ and R² together with the nitrogen atom form a bridgedheterocyclic ring, examples of such groups include7-aza-bicyclo[2.2.1]hept-7-yl or 2-aza-bicyclic[2.2.2]oct-8-yl.

Preferably, the group NR¹R² is a tertiary amino group; more preferably a4-8 membered heterocyclic ring which may be substituted by 1-4 methylgroups; or an optionally substituted 5- or 6-membered heterocycle. Inthe most preferred embodiment of the invention, NR¹R² is a pyrrolidinylgroup.

Each R⁶ is the same or different and is independently selected from thegroup consisting of hydroxy, C₁₋₂alkyl, C₁₋₃alkoxy, halo, C₂₋₃alkenyl,benzyl, and —C(R^(a))NOR^(b), wherein R^(a) and R^(b) are eachindependently selected from the group consisting of hydrogen, methyl,methoxymethyl, methoxymethoxy, and methoxyethoxy. Typically, R⁶ is asubstituent of the phenyl ring of formula (I) that is preferably locatedin the ortho position relative to the M substituent. Preferred examplesof R⁶ include hydroxy, methoxy, methoxymethoxy, methoxyethoxy, andmethoxymethyl. Most preferably, R⁶ is methoxyl. In the formula, n is 1,2, 3, or 4.

QY is a bicyclic fused heterocyclic ring wherein Q and Y are each onering of said bicyclic fused heterocyclic group, wherein said Y ringcontains from 1 to 3 nitrogens and is bound to the phenyl ring offormula (I) through a nitrogen, and said Q ring is a 5 or 6 memberedaryl or heteroaryl having a group ZR³ bound to the Q ring.

The fused bicyclic heterocyclic group QY is preferably a 5,5; 5,6; 6,5;or 6,6 bicyclic heterocyclic system.

In QY group, Q is conveniently an aromatic ring such as benzene,thiophene, furan or pyridine. Y, in QY, is linked via a nitrogen atomtherein to the rest of the molecule in formula (I) and optionallycontains a further 1 or 2 nitrogen atoms. Preferably, the ring alsocontains a carbonyl group adjacent to the linking nitrogen atom.

When Y is a 5-membered ring, it contains either two carbonyl groups or acarbonyl and a methylene group, in addition to the nitrogen atom. When Yis a 5-membered ring, then preferably Q is a benzene ring, and morepreferably QY is an isoindole-1,3-dione.

When Y is a 6-membered ring, it preferably contains a carbonyl group andeither two additional nitrogen atoms or a single additional nitrogen anda moiety selected from the group consisting of carbonyl, thiocarbonyl,and methylidene. Said moiety can be optionally substituted by a memberselected from the group consisting of methyl, methoxy, methylthio, andS(O)CH₃. When Y is a 6-membered ring, Q is preferably a benzene orthiophene ring.

Examples of suitable QY groups include isoindole-1,3-dione,2,3-dihydro-isoindole-1-one, 3-H-benzo[d](1,2,3)triazin-4-one,3-H-quinazolin-4-one, 1-H-quinazoline-2,4-dione,3-H-thieno[2,3-d]-1-triazine-4-one, 3-H-thieno[2,3d]pyrimidin-4-one,3-H-thieno[3,2-d]pyrimidin-4-one,2-thioxo-2,3-dihydro-1-H-thieno[3,2-d]pyrimidine-4-one,2-methylsulphanyl-3H-thieno[3,2-d]pyrimidin-4-one.

Z is selected from the group consisting of a direct bond, NH, OCH₃, O,S, and CH₂. Preferably, examples of suitable groups Z include a bond,oxygen, sulphur, CH₂ or NH. Most preferably, the group Z is a bond or anoxygen atom.

R³ is a group selected from the group consisting of aryl, alk-2-en-1-yl,cycloalkyl and cycloalk-2-en-1-yl and wherein said aryl, alk-2-en-1-yl,cycloalkyl, and cycloalk-2-en-1-yl are optionally substituted from 1 to3 times with a substituent selected from the group consisting of C₁₋₃alkyl, halo, amino, alkylamino, dialkylamino, hydroxy, C₁₋₃ alkoxy,cyano, trifluoromethyl, and methylthio groups. Examples of suitable R³groups include phenyl optionally substituted by one or two groupsselected from halogen (e.g. fluorine, chlorine or bromine), hydroxy,C₁₋₃ alkoxy (e.g. methoxy), C₁₋₄ alkyl (e.g., methyl, ethyl, t-butyl,and haloalkyls such as trifluoromethyl), and cyano. Also, R³ can be C₅₋₇cycloalkyl (e.g., cyclohexyl), C₅₋₇ cycloalk-2-en-1-yl (e.g.,cyclohex-2-en-1-yl or cyclopent-2-en-1-yl), or C₃₋₆ alk-2-en-1-yl (e.g.,3-methyl-prop-2-en-1-yl or 2-methyl-prop-2-en-yl). Preferably, the groupR³ is phenyl or a substituted phenyl group; and most preferably R³ isphenyl.

Examples of suitable preferred compounds according to the inventioninclude those described in the Examples herein.

Specifically, most preferred compounds of the invention include:

-   3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethyl)-phenyl]-7-phenyl-3H-benzo[d][1,2,3]triazin-4-one;-   3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-phenyl-3H-thieno[3,2-d]pyrimidin-4-one;    and physiologically acceptable acid addition salts thereof.

The compounds of formula (I) form acid addition salts and can be dosedas such. For use in medicine acid addition salts of a compound offormula (I) will be those formed with physiologically acceptableinorganic and organic acids. Examples of such suitable acids includehydrochloric, hydrobromic, phosphoric, acetic, ascorbic, benzoic,citric, fumaric, lactic, maleic, mandelic, methanesulphonic, salicylic,succinic, and tartaric.

Other acid addition salts of the compounds of formula (I) may however beuseful in the preparation and/or isolation of a compound of formula (I)or a physiologically acceptable salt thereof and are contemplated asbeing part of the invention herein.

Compounds of the present invention are antagonists of a human 11CByreceptor disclosed in Nature, 400, 261-265 (1999). Accordingly, thesecompounds are believed to have a role in the treatment (preventing,prophylaxis, ameliorating, or correcting) of dysfunctions or diseases,including, but not limited to, infections such as bacterial, fungal,protozoan and viral infections, particularly infection caused by HIV-1or HIV-2; pain; cancers; diabetes; obesity; feeding abnormalities, suchas anorexia and bulimia; drinking abnormalities (too much or too littleliquid consumption); asthma; Parkinson's disease; both acute andcongestive heart failure; hypertension; urinary retention; osteoporosis;angina pectoris; myocardial infarction; ulcers; allergies; benignprostatic hypertrophy; psychotic and neurological disorders, includinganxiety, schizophrenia, depression (major), manic depression (bi-polardepression), delirium, dementia, and/or severe mental retardation; anddyskinesias (such as Huntington's disease or Gilles de la Tourette'ssyndrome, among others), hereinafter all of the above conditions(diseases, dysfunctions, abnormalities, etc.) are referred tocollectively herein as “the Disorders”. Preferably, this aspect of theinvention provides for the treatment (including prophylaxis) of one ormore of the Disorders selected from diabetes, major depression, manicdepression (bipolar disorder), anxiety, schizophrenia and sleepdisorders. Preferred among these disorders are obesity, diabetes(especially diabetes mellitus), major depression, and anxiety.

It has been reported that over-expression of MCH gene in mouse isassociated with obesity and insulin resistance (Ludwig DS et al.Melanin-concentrating hormone overexpression in transgenic mice leads toobesity and insulin resistance. J Clin Invest 2001 107(3): 379-386). Invitro data revealed that MCH stimulates insulin secretion in both CRI-G1and RINm5F cell-lines (Tadayyon M et al. Expression ofmelanin-concentrating hormone receptors in insulin-producing cells: MCHstimulates insulin release in RINm5F and CRI-G1 cell-lines. BBRC 2000275: 709-712).

In this patent we also disclose that surprisingly MCH contributes toblood glucose regulation by increasing plasma glucagon levels inconscious instrumented rats. In addition, we claim the use of 11CByantagonists to inhibit MCH-induced hyperglycemia by reducing MCH-inducedhyperglucagonemia. Thus, in addition to other important impications of11CBy antagonists in obesity and neurological indications, suchantagonists will have therapeutic implication for the treatment ofdiabetes mellitus.

The administration of such compounds to a mammal may be by way of oral(including sub-lingual), parenteral, nasal, rectal or transdermaladministration. An amount effective to treat the Disorders herein beforedescribed depends on the usual factors such as the nature and severityof the disorders being treated and the weight of the mammal. However, aunit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, forexample an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20,30, 40, 50, 100, 200, 300 and 400 mg of the active compound. Unit doseswill normally be administered once or more than once per day, forexample 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day,such that the total daily dose is normally in the range, for a 70 kgadult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range ofapproximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, forexample 1 to 6 mg/kg/day.

It is greatly preferred that compounds of formula (I) and orphysiologically acceptable salts or solvates thereof are administered inthe form of a unit-dose composition, such as a unit dose oral (includingsub-lingual), nasal, rectal, topical or parenteral (especiallyintravenous) composition.

Such compositions are prepared by admixture and are suitably adapted fororal or parenteral administration, and as such may be in the form oftablets, capsules, oral liquid preparations, powders, granules,lozenges, reconstitutable powders, injectable and infusable solutions orsuspensions or suppositories. Orally administrable compositions arepreferred, in particular shaped oral compositions, since they are moreconvenient for general use.

Tablets and capsules for oral administration are usually presented in aunit dose, and contain conventional excipients such as binding agents,fillers, diluents, tabletting agents, lubricants, disintegrants,colourants, flavourings, and wetting agents. The tablets may be coatedaccording to well-known methods in the art. Suitable fillers for useinclude cellulose, mannitol, lactose and other similar agents. Suitabledisintegrants include starch, polyvinylpyrrolidone and starchderivatives such as sodium starch glycollate. Suitable lubricantsinclude, for example, magnesium stearate. Suitable pharmaceuticallyacceptable wetting agents include sodium lauryl sulphate.

These solid oral compositions may be prepared by conventional methods ofblending, filling, tabletting or the like. Repeated blending operationsmay be used to distribute the active agent throughout those compositionsemploying large quantities of fillers. Such operations are, of course,conventional in the art.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups, or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel or hydrogenated edible fats;emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample, almond oil, fractionated coconut oil, oily esters such asesters of glycerine, propylene glycol, or ethyl alcohol; preservatives,for example methyl or propyl p-hydroxybenzoate or sorbic acid; and ifdesired conventional flavouring or colouring agents.

Oral formulations also include conventional sustained releaseformulations, such as tablets or granules having an enteric coating.

For parenteral administration, fluid unit dose forms are preparedcontaining the compound and a sterile vehicle. The compound, dependingon the vehicle and the concentration, can be either suspended ordissolved. Parenteral solutions are normally prepared by dissolving thecompound in a vehicle and filter sterilising before filling into asuitable vial or ampoule and sealing. Advantageously, adjuvants such asa local anaesthetic, preservatives and buffering agents are alsodissolved in the vehicle. To enhance the stability, the composition canbe frozen after filling into the vial and the water removed undervacuum.

Parenteral suspensions are prepared in substantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and is sterilised by exposure to ethylene oxide beforesuspending in the sterile vehicle. Advantageously, a surfactant orwetting agent is included in the composition to facilitate uniformdistribution of the compound of the invention.

As is common practice, the compositions will usually be accompanied bywritten or printed directions for use in the medical treatmentconcerned.

Compounds of the present invention may be employed alone or inconjunction with other compounds, such as therapeutic compounds.

No adverse toxicological effects are expected for the compounds of theinvention, when administered in accordance with the invention.

Accordingly, in a further aspect, the present invention provides apharmaceutical composition for use in the treatment and/or prophylaxisof one or more of the Disorders which comprises a compound of thisinvention, or a physiologically acceptable salt or solvate thereof, anda pharmaceutically acceptable carrier.

The present invention also provides a method of treatment and/orprophylaxis of one or more of the Disorders comprising administering tothe sufferer in need thereof an effective or prophylactic amount of acompound of this invention, or a physiologically acceptable salt orsolvate thereof.

In a further aspect the invention provides the use of a compound of thisinvention, or a physiologically acceptable salt or solvate thereof, forthe manufacture of a medicament for the treatment and/or prophylaxis ofone or more of the Disorders. In a still further aspect the inventionprovides a compound of formula (I), or a physiologically acceptable saltor solvate, thereof as a therapeutic agent, in particular for thetreatment and/or prophylaxis of one or more of the Disorders.

A further aspect of the invention provides processes for the preparationof compounds of formula (I). Unless stated otherwise, R¹, R², R³, R⁶, Z,Q, Y, M, and L are as defined in formula (I).

Thus compounds of formula (I) wherein Y is a 5 membered ring containingtwo carbonyl groups may be prepared by reaction of an aniline of formula(II)

wherein R⁶, n, M, L, R¹ and R² have the meanings defined in formula (I)or are protected derivatives thereof with appropriate anhydride (III),orthodicarboxylic acid (IV) or imide (V) set forth below

wherein R³, Z and Q have the meanings defined in formula (I), underconventional conditions for the formation of the required imide group Y.

The reaction is carried out using a coupling agent, e.g.,dicyclohexylcarbodiimide, conveniently on a resin support, in anappropriate solvent such as a halohydrocarbon, e.g., dichloromethane oran amide such as N,N-dimethylformamide or a mixture thereof andoptionally in the presence of a tertiary organic base such as4-dimethylaminopyridine or diethylisopropylamine, which is alsoconveniently on a resin support.

Compounds of formula (I) where Y is a 5-membered ring containing asingle carbonyl group may be prepared by reduction of the correspondingcompound of formula (I) wherein Y is a 5 membered ring containing 2carbonyl groups, using a conventional two step reduction process. Forexample, reduction with a suitable hydride such as a borohydridefollowed by treatment with a hydrogen donor such as triethylsilane inthe presence of a suitable acid, e.g., trifluoroacetic acid.

Compounds of formula (I) wherein Y is a 6-membered heterocycle may beprepared by cyclisation of the compound of formula (VI)

wherein R³Z, Q, R⁶, n, M, L, R¹ and R² have the meanings defined informula (I). Thus compounds of formula (I) wherein Y is apyrimidin-4-one moiety may be prepared by heating a compound of formula(VI) with formic acid or an appropriate orthoester e.g.triethylorthoformate in a suitable solvent such as a halohydrocarbone.g. dichloroethane followed by treatment with a strong base such as1,8-diazabicyclo[5.4.0]undec-7-one (DBU).

Compounds of formula (I) wherein Y is a pyrimidine-2,4-dione may beprepared by treating the amine (VI) with a carboxylating agent such ascarbonyl-diimidazole and a strong base such as DBU in a suitable aproticsolvent such as dichloroethane.

Compounds of formula (I) wherein Y is a 1,2,3-triazin-4-one may beprepared by diazotisation of the compound of formula (VI) followed bytreatment with a strong base, e.g. DBU. Thus, the reaction may becarried out by reacting a solution of amine (VI) in a solvent such asdichloromethane with an alkyl nitrite, e.g., butyl or amyl nitrite, inthe presence of a suitable organic carboxylic acid, e.g.,trifluoroacetic acid followed by addition of the strong base.

Compounds of formula (I) wherein Y is a pyrimidine ring containing athiocarbonyl group or an alkylthio substituent at the 2 position may beprepared from the thiourea (VII)

wherein R³Z, Q, R⁶, n, M, L, R¹ and R² have the meanings defined informula (I) or are protected derivatives thereof and Alk is C₁₋₄alkyl.Thus, compounds of formula (I) wherein Y contains a 2-thiocarbonyl groupmay be prepared by heating the thiourea (VII) in a suitable high boilingsolvent such as an aromatic hydrocarbon, e.g., toluene.

Compounds of formula (I) wherein Y is a pyrimidinone having an alkylthiogroup at the 2 position may be prepared by reaction of compound (VII)with the appropriate alkyl halide in an aprotic polar solvent such asDMF and in the presence of a suitable base such as a tertiary amine oran alkali or alkaline metal earth carbonate, e.g., sodium carbonate orpotassium carbonate.

Compounds of formula (I) wherein Y is a pyridmidinone derivative,unsubstituted at the 2-position may be prepared from the correspondingpyrimidinone having an alkylthio group at the 2-position by reactionwith Raney nickel in a solvent such as an alkanol, e.g., ethanol.

Compounds of formula (I) may also be prepared by reaction of a compoundof formula (VIII)

wherein Q, Y, R⁶, n, M, L, R¹ and R² have the meanings defined informula (I) or a group convertible thereto and T is a leaving ordisplacable group, e.g., halogen, with a compound capable of introducingthe group R³Z.

Thus, compounds of formula (I) wherein Z is a bond and R³ is an arylgroup may be prepared from the halide of formula (VIII) with theappropriate arylboronic acid using a Suzuki coupling reaction or withthe appropriate aryl-tin reagent using a Stille displacement reaction.

Compounds of formula (I) wherein Z is a methylene group may be preparedby treating a compound of formula (VIII) with an appropriate organo zincor organo magnesium compound in the presence of a palladium catalyst.The reaction is carried out in an aprotic solvent such as an ether(e.g., THF) and the organo zinc or organo magnesium compound is onecapable of introducing the group R³CH₂.

Compounds of formula (I) wherein Z is NH or NCH₃ may be prepared byreacting the halide of formula (VIII) with the appropriate amine R³NH₂or R³NHCH₃ in the presence of a palladium catalyst under standardBuchwald conditions.

Compounds of formula (I) wherein Z is sulphur may be prepared byreaction of a compound of formula (VIII) with the thiol R³SH in thepresence of a suitable base such as an alkali metal hydride in anaprotic solvent such as an ether, e.g., THF. Similarly, compounds offormula (I) wherein Z is oxygen may be prepared by the reaction of thecompound of formula (VIII) with the compound R³OH in the presence of analkali metal hydride and an aprotic solvent, e.g., DMF.

The anilines of formula (II) are either known compounds or may beprepared by analogous methods described for preparing the knowncompounds. Thus, compounds of formula (II) wherein L and (R⁶)_(n) are toform a cyclic group as defined in formula (I) may be prepared using theprocedures described in WO 01/2577 A2.

Compounds of formula (II) wherein M is O or S may be prepared byreaction of the nitrochlorobenzene (X)

wherein R⁶ and n has the meanings defined in formula (I) or is a groupconvertible thereto, with the compound (XI)HMLNR¹R²  (XI)wherein M is O or S and L, R¹ and R² have the meaning defined in formula(I) or R¹ and R² are protected derivatives thereof, in the presence of astrong base such as sodium hydride in a polar aprotic solvent such asDMF, followed by reduction of the nitro group to amino usingconventional means such as hydrogen and a palladium catalyst or iron andammonium chloride.

Compounds of formula (II) wherein M is CH₂ may be prepared by reactingan activated derivative of the acid (XII)

wherein R⁶ and n have the meanings as defined in formula (I) and L₁ is a1 or 2 membered alkylene chain with the amine HNR¹R² wherein R¹ and R²have the meanings defined in formula (I) followed by reduction of theresultant amide with borane in an aprotic solvent such astetrahydrofuran and then reduction of the nitro group using conventionalprocedures as documented above.

Alternatively compounds of formula (I) may be prepared by alkylation ofthe amino R¹R²NH wherein R¹ and R² have the meaning defined in formula(I) or are protected derivatives thereof by reaction with a compound offormula (XIII)

wherein R⁶, n, M and L have the meanings defined in formula (I) and halis a halogen in the presence of a suitable base and a polar solvent suchas DMF, and subsequent generation of the required primary amino group byreaction of the corresponding nitro group using a conventionalprocedure.

The compounds of formula (X), (XI), (XII) and (XIII) are either knowncompounds or may be prepared by analogous methods to those used toprepare the known compounds.

The anhydride (III) is either a known compound or may be prepared byanalogous methods to those described for preparing known compounds. Thusthe compounds may be prepared from the anhydride (IX)

wherein Q has the meaning in formula (I) and T is a leaving group, usingthe same reaction conditions to introduce the group R³Z as describedabove for the preparation of compounds of formula (I) from the compoundsof formula (VIII).

The ortho dicarboxylic acid (IV) and the imide (IV) may also be preparedin an analogous manner to that for preparing the anhydride (III) fromthe compound of formula (IX).

Compounds of formula (VI) may be prepared by the process outlined belowwherein

In the above formulae the groups M, L, R¹, R², R³, R⁶, n, Z and Q havethe meaning defined in formula (I) and T is a displaceable group asdefined in formula (VIII).

The condensation of an activated derivative, e.g., acid chloride of theacids (XIV) or (XVI) with the amine (II) to give amides (XV) and (XVII)may be carried out under conventional conditions for preparing amidesfrom anilines and a carboxylic acid.

Compounds of formula (XVII) may be converted into the required compound(XV) using the conditions described above for converting a compound offormula (VIII) into a compound of formula (I).

The carboxylic acid (XIV) may be prepared from the correspondingcarboxylic acid (XVI) or a protected derivative thereof by theconditions previously described above for introducing the group R³Z bydisplacement of the group T.

Alternatively, compounds of formula (VI) may be prepared by the processoutlined below wherein R¹, R², R³, R⁶, Z, Q, M, and L are as defined informula (I).

Compounds of formula (VII) may be prepared by the process as outlinedbelow wherein R¹, R², R³, R⁶, Z, Q, M, and L are as defined in formula(I), and Alk is C₁₋₄ alkyl.

Compounds of formula (VIII) may be prepared from the aniline (II) andthe anhydride (IX) or carboxylic acid (XVI) using the general processesdescribed above for preparing the corresponding compounds of formula (I)from the aniline (II).

The acids of formula (XIV) are either known compounds or can be preparedby analogous processes to those used for preparing the known compounds.Alternatively, they may be prepared by the process outlined belowwherein wherein R³, Z, and Q are as defined in formula (I).

In the above processes, it will be appreciated that it may be necessaryto carry out the reactions wherein one or more of the groups R³, Z, Q,X, M, L, R⁶, R¹ or R² may need to be present in a protected form andthen the protecting group(s) removed. The need for such protection willbe well understood by those skilled in the art and such protection isclearly within the scope of the present invention.

Acid addition salts of compounds of formula (I) may be prepared in aconventional manner by treating the compound of formula (I) with theappropriate inorganic or organic acid. For example, by addition of theacid, optionally as a solution in an organic solvent to a solution ofthe free base in a suitable solvent.

Compounds for use in this invention and their preparation areillustrated in the following Examples and Tables.

These Examples illustrate general procedures and sources of chemicalsutilised to prepare compounds whose structures are shown in the Tablesof data which follow the Examples. In the case of Examples prepared asmembers of a coupled array, the synthetic origin of all startingcomponants of the array are shown in the Examples. Rather than detailingthe experimental procedure for each case, the method by which individualmembers of the array were prepared is indicated in a Table by referenceto a related Example. Mass spectral characterisation of all Examples isprovided in the tables of data. Additional characterisation is providedfor selected representative Examples with full experimental procedures.

EXAMPLE A12-[4-(2-Diisopropylamino-ethoxy)-3-methoxy-phenyl]-5-phenyl-isoindole-1,3-dione

4-Bromophthalic anhydride [Apin] (2.27 g, 10 mmol) was dissolved in1,2-dichloromethane (8 ml), and pyridine (10 mmol, 0.81 ml) was added,followed by 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine [PatentWO-9901127] (2.44 g, 10 mmol) and a catalytic amount of4-dimethylaminopyridine [Aldrich]. The mixture was heated for 16 h at85° C. The mixture was evaporated in vacuo and applied to a BiotageFlash40M cartridge, (eluting with dichloromethane-methanol-aqueousammonia) to give the5-bromo-2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-isoindole-1,3-dione3.05 g, 68%, as the trifluoroacetate salt;

¹H NMR (CDCl₃): δ 1.06 (12H, bd), 2.92 (2H, bt), 3.05 (2H, bm), 3.88(3H, s), 3.99 (2H, bt), 6.89-7.03 (3H, m), 7.78 (1H, d), 7.91 (1H, dd)8.06 (1H, d); m/z [AP+] 475, 477 (M+H⁺, 100%).

A solution of this material (331 mg, 0.7 mmol) in benzene (46 ml),ethanol (9 ml) and aqueous sodium carbonate (2M, 9 ml) was degassed andtreated with phenyl boronic acid (85 mg, 0.7 mmol) andtetrakis(triphenylphosphine)palladium[0] (20 mg). The mixture wasbrought to reflux (80° C.) for 16 hours then cooled and filtered throughfilter-aid, washing with dichloromethane. The filtrate was evaporatedand the residue subjected to flash chromatography on silica gel (elutingwith methanol-dichloromethane-aqueous ammonia) to obtain the titlecompound;

¹H NMR (CDCl₃): δ 1.06 (12H, d), 2.94 (2H, t), 3.07 (2H, m), 3.89 (3H,s), 4.00 (2H, t), 6.95-7.00 (3H, m), 7.35-7.52 (3H, m), 7.67 (2H, dd),7.99 (2H, s), 8.15 (1H, s),

which crystallised on treatment with 1M HCl in ether to a white solid.

EXAMPLE A25-Benzyl-2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-isoindole-1,3-dione

A mechanically agitated piece of zinc foil [Aldrich] (99.99%, 0.1 mmthick, 0.5 g), in dry THF under argon was treated with trimethylsilylchloride (20 ul), then after ten minutes, 1,2-dibromoethane (80 ul). Themixture was stirred for 20 minutes then a solution of benzyl bromide (5mmol, 0.59 ml) and THF (4.4 ml) introduced. The mixture was stirred at0° C. for 2 h then warmed to RT for 1 h. A 2.6 ml portion of theresulting solution was added to a mixture of5-bromo-2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-isoindole-1,3-dione[Example A1], tetrakis(triphenylphosphine)palladium[0] (5 mol %, 120mg), and THF (3 ml). The mixture was heated at 60° C. for 16 h. Theresulting solution was evaporated and partially purified by flashchromatography (dichloromethane-methanol-aqueous ammonia) on silica gelbefore being further purified by reverse phase chromatography (aq.MeCN/TFA) to give the title compound as the trifluoroacetate salt;

¹H NMR (CDCl₃): δ 1.45 (12H, m), 3.52 (2H, t), 3.84 (2H, s), 3.85 (3H,sm), 4.15 (2H, m), 4.74 (2H, t), 5.80 (1H, bs), 6.92-7.04 (3H, m),7.19-7.35 (5H, m), 7.60 (1H, dd), 7.75 (1H, s), 7.83 (1H, d).

EXAMPLE A32-[4-(2-Diisopropylamino-ethoxy)-3-methoxy-phenyl]-5-phenylamino-isoindole-1,3-dione

A mixture of palladium II acetate (7.5 mg, 0.04 mmol),2-(dicyclohexylphosphino)biphenyl [Digital] (0.06 mmol, 21 mg) andcesium carbonate (205 mg, 0.63 mmol) in 1,4-dioxane (5 ml) was sonicatedunder argon for 40 minutes. To this suspension was added a mixture of5-bromo-2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-isoindole-1,3-dione[Example A1] (200 mg, 0.42 mmol) and aniline (0.42 mmol, 39 mg) in1,4-dioxane (1 ml). The mixture was heated at 85° C. for 16 h then thecooled mixture filtered through filter-aid and the filtrate evaporated.The residue was subjected to purification by preparative reverse phasechromatography (aq. MeCN, TFA) to give the title compound as thetrifluoroacetate salt;

¹H NMR (CDCl₃): δ 1.46 (12H, m), 3.51 (2H, t), 3.80-3.87 (2H, m), 3.86(3H, s), 4.50 (2H, t), 6.4 (1H, bs), 6.94-7.03 (3H, m), 7.17-7.24 (4H,m), 7.38-7.44 (3H, m), 7.75 (1H, d).

EXAMPLE A42-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-phenoxy-isoindole-1,3-dionehydrochloride

To a solution of the 1-(2-hydroxyethyl)-pyrrolidine [Aldrich], (1.87 ml,16 mmol) in dimethylformamide was added portionwise sodium hydride [60%dispersion in oil, (544 mg, 16 mmol). After stirring at room temperaturefor 10 minutes a solution of 1-chloro-2-methoxy-4-nitro-benzene[Avocado] (3 g, 16 mmol) in dimethylformamide (10 ml) was addeddropwise. The reaction mixture was left stirring at room temperature for16 hrs then concentrated. The residue was dissolved in ethyl acetate(200 ml) and washed with water (3×50 ml). The organic phase was driedwith magnesium sulphate, evaporated and the residue purified by flashchromatography on silica gel using dichloromethane-aq. ammonia-methanolas eluent to afford 1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-pyrrolidineas a brown oil.

¹H NMR (CDCl₃): δ1.82 (4H, m), 2.65 (4H, m), 3.01 (2H, t), 3.94 (3H, s),4.24 (2H, t), 6.92 (1H, d), 7.74 (1H, d), and 7.89(1H, dd); MS (AP+ve):m/z 267 [M+H]⁺.

To a solution of 1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-pyrrolidine(2.3 g, 8.6 mmol) in ethanol (100 ml) was added 10% Pd/C (50 mg). Themixture was stirred at room temperature under an atmosphere of hydrogenat atmospheric pressure for 16 h, then filtered through celite and thefiltrate concentrated to give the corresponding aniline;3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine, as a brown solid.

¹H NMR (CDCl₃): δ 1.80 (4H, m), 2.62 (4H, m), 2.89 (2H, t), 3.5 (2H,brs), 3.80 (3H, s), 4.06 (2H, t), 6.20 (1H, dd), 6.29 (1H, d) and 6.75(1H, d); MS (AP+ve): m/z 237 [M+H]⁺.

4-Phenoxy-phthalic acid [J. Org. Chem. (1977), 42(21), 3425-31] (893 mg,3.5 mmol) was dissolved in DMF (30 ml) and polymer boundN-cyclohexylcarbodiimide [Argonaut Technologies](1.69 mol. eq./g, 4.1 g)was added, followed by a solution of3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (817 mg, 3.5 mmol) inDMF (5 ml) and a catalytic amount of DMAP. The mixture was stirred for16 h at ambient temperature. The resin was filtered off over filter-aid,washing with dichloromethane. The filtrate was evaporated in vacuo andpurified by chromatography using a Biotage Flash40M cartridge (elutingwith dichloromethane-methanol-aqueous ammonia). The resulting yellow oilwas dissolved in CHCl₃ and treated with ethereal HCl (1 M, 2 ml) to givea yellow solid. Recrystallisation from methanol/diethyl ether gave thetitle compound as an off-white solid (328 mg, 0.7 mmol);

¹H NMR (CDCl₃): δ 12.82 (1H, br), 7.88 (1H, dd), 7.45-7.27 (5H, m),7.13-6.94 (5H, m), 4.57 (2H, t), 3.91 (2H, br), 3.86 (3H, s), 3.50 (2H,br), 3.07 (2H, br), 2.26-2.07 (4H, m, br).

EXAMPLE A52-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-phenylamino-isoindole-1,3-dione

3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine [Example A4] was usedin the same manner as4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine in the procedure ofExample A1 to form5-bromo-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione;

¹H NMR (CDCl₃): δ 2.05 (4H, m), 3.15 (4H, bs), 3.32 (2H, t), 3.87 (3H,s), 4.43 (2H, t), 6.92-7.06 (3H, m), 7.80 (1H, d), 7.92 (1H, dd), 8.07(1H, d).

This material was used in the procedure of Example A3 in place of5-bromo-2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-isoindole-1,3-dioneto afford the title compound as a trifluoroacetate salt;

¹H NMR (CDCl₃): δ 2.12 (4H, bd), 2.5 (1H, bs), 3.08 (2H, bm), 3.55 (2H,m), 3.85 (3H, s), 3.88 (2H, m), 4.12 (2H, t), 6.96 (3H, m), 7.17-7.26(4H, m), 7.39-7.44 (3H, m), 7.73 (1H, d) 12.5 (1H, bs).

EXAMPLE A65-Benzyl-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

5-Bromo-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione[Example A5] was used in the same manner as5-bromo-2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-isoindole-1,3-dionein the procedure of Example A2 to afford the title compound as thetrifluoroacetate salt;

¹H NMR (CDCl₃): δ 2.14 (4H, bm), 3.10 (2H, m), 3.59 (2H, bt), 3.84 (3H,s), 3.91 (2H, m), 4.15 (2H, d), 4.43 (2H, t), 6.2 (1H, bs), 6.94-6.99(3H, m), 7.18-7.74 (7H, m), 7.85 (1H, d).

EXAMPLE A72-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-(phenylthio)-isoindole-1,3-dione

4-Fluorophthalic anhydride [Acros] (0.84 g, 5 mmol) was dissolved indichloromethane (30 ml) and polymer bound N-cyclohexylcarbodiimide[Argonaut Technologies](1.69 mol. eq./g, 3 g) was added, followed by asolution of 3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine [ExampleA4] (1.18 g, 5.0 mmol) and a catalytic amount of4-dimethylaminopyridine. The mixture was stirred for 16 h at ambienttemperature. The resin was filtered off over filter-aid, and washed withdichloromethane. The filtrate was evaporated in vacuo and purified bychromatography using a Biotage Flash40M cartridge, eluting withdichloromethane-methanol to give the5-fluoro-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione;

¹H NMR (CDCl₃): δ 2.12 (4H, m), 3.32 (4H, bs), 3.44 (2H, t), 3.86 (3H,s), 4.48 (2H, t), 6.93-7.03 (3H, m), 7.45 (1H, dt), 7.60 (1H, dd), 7.90(1H, dd); m/z [AP+] 458 (M+H⁺, 100%).

A portion of this material (96 mg, 0.25 mmol) was added to a stirredmixture of thiophenol (55 mg, 0.5 mmol) and sodium hydride (60% oildispersion, 16 mg/0.4 mmol) in DMF (2 ml) and the mixture warmed to 50°C. The solution was cooled, evaporated and the residue purified byreverse phase chromatography (acetonitrile-water-TFA) to give the titlecompound as the trifluoroacetate salt, an off white solid;

¹H NMR (CDCl₃): δ 1.85 (4H, m), 2.74 (4H, m), 3.02 (2H, t), 3.85 (3H,s), 4.22 (2H, t), 6.89-6.97 (3H, m), 7.44-7.60 (7H, m), 7.76 (1H, d).

EXAMPLE A85-[(4-chlorophenyl)thio]-2-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-isoindole-1,3(2H)-dione

Using the method of Example A7 but utilising 4-chlorothiophenol[Aldrich] in place of thiophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A95-[(3-methoxyphenyl)thio]-2-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-isoindole-1,3(2H)-dione

Using the method of Example A7 but utilising 3-methoxythiophenol[Aldrich] in place of thiophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A105-[(4-hydroxyphenyl)thio]-2-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-isoindole-1,3(2H)-dione

Using the method of Example A7 but utilising 4-hydroxythiophenol[Aldrich] in place of thiophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A115-[(4-fluorophenyl)thio]-2-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-isoindole-1,3(2H)-dione

Using the method of Example A7 but utilising 4-fluorothiophenol[Aldrich] in place of thiophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A125-[(4-aminophenyl)thio]-2-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-isoindole-1,3(2H)-dione

Using the method of Example A7 but utilising 4-aminothiophenol [Aldrich]in place of thiophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A132-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-5-{[4-(trifluoromethyl)phenyl]thio}-1H-isoindole-1,3(2H)-dione

Using the method of Example A7 but utilising 4-trifluoromethylthiophenol[Aldrich] in place of thiophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A145-[(4-methoxyphenyl)thio]-2-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-isoindole-1,3(2H)-dione

Using the method of Example A7 but utilising 4-methoxythiophenol[Aldrich] in place of thiophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A155-(4-Chloro-phenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

4-Fluorophthalic anhydride (42 mg, 0.25 mmol) in DMF (0.5 ml) wastreated with 4-chlorophenol (32 mg, 0.25 mmol) and sodium hydride (60%oil disp. 10 mg, 0.25 mmol). The mixture was heated to 140° C. for 15minutes then cooled, dichloromethane (5 ml) added,3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine [Example A4] (59 mg,0.25 mmol) introduced, polymer bound N-cyclohexylcarbodiimide (1.69 mol.eq./g, 0.5 g) added, polymer bound diethylisopropylamine resin [ArgonautTechnologies] (3.49 mol. eq./g, 0.2 g) added and the mixture stirred atRT for 16 hours. The solution was filtered through filter-aid, washingwith dichloromethane, the combined organic phases evaporated andpurified by reverse phase chromatography (acetonitrile-water-TFA) togive the title compound as its trifluoroacetate salt;

¹H NMR (CDCl₃): δ 2.1 (2H, bs), 2.25 (2H, bs), 3.05 (2H, bs), 3.55 (2H,bs), 3.83 (3H, s), 3.89 (2H, bs), 4.55 (2H, bs) 6.97-7.19 (5H, m), 7.39(1H, d), 7.47 (1H, s), 7.70 (2H, d), 7.93 (1H, d), 12.7 (1H, bs).

EXAMPLE A165-(4-fluorophenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-1H-isoindole-1,3(2H)-dione

5-Nitro-2-phenylisoindole-1,3-dione (5.9 g, 22 mmol) was dissolved inDMF (40 ml) and sodium 4-fluorophenolate (3.1 g, 23.1 mmol) was added.The resulting mixture was stirred at 100° C. for 2 hours under an argonatmosphere. The mixture was allowed to cool to RT then poured into 4%aqueous HCl. The yellow precipitate which formed was filtered off,washed with water and recrystallised (DCM/TBME) to yield(4-fluorophenoxy)-2-phenylisoindol-1,3-dione (2.4 g, 41%); MS [APCI⁺]334 (100%, M+H⁺).

This phthalimide (1.4 g, 4.2 mmol), ethyleneglycol (20 mL) and 25%aqueous NaOH (4 mL) were heated at 140° C. for 16 hours. The resultingmixture was poured into 1M aqueous HCl to give an orange precipitate.This was washed with 0.1 M aqueous HCl and water then dried to afford4-(4-fluorophenoxy)phthalic acid in 65% yield; m/z [APCI⁻] 275 (20%,M−H⁻), 231 (100%).

Using the procedure of Example A4 but utilising4-(4-fluorophenoxy)phthalic acid in place of 4-phenoxyphthalic acid gavethe title compound which crystallised from ethereal hydrochloric acid togive a white solid.

Also by the method of Example A15 but using 4-fluorophenol in place of4-chlorophenol to give the title compound as the trifluoroacetate salt.

EXAMPLE A175-(4-Trifluoromethyl-phenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 4-trifluoromethylphenol[Aldrich] in place of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A185-(4-Fluoromethyl-phenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 4-fluoro-3-chlorophenol[Aldrich] in place of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A195-(3-Fluoro-phenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 3-fluorophenol [Aldrich]in place of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A205-(3-Chloro-phenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 3-chlorophenol [Aldrich]in place of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A215-(3-tert-Butyl-phenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 3-tert-butylphenol[Aldrich] in place of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A225-(3-Methoxy-phenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 3-methoxyphenol [Aldrich]in place of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A235-(3-Methyl-phenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 3-methylphenol [Aldrich]in place of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A245-(4-Methyl-phenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 4-methylphenol [Aldrich]in place of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A255-(4-Cyano-phenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 4-cyanophenol [Aldrich] inplace of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A265-(2-Cyano-phenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 2-cyanophenol [Aldrich] inplace of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A272-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-5-[2-(methylthio)phenoxy]-1H-isoindole-1,3(2H)-dione

Using the method of Example A15 but utilising 2-(methylthio)phenol[Aldrich] in place of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A285-(2-Bromo-phenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 2-bromo-phenol [Aldrich]in place of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A295-(2-Chloro-phenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 2-chloro-phenol [Aldrich]in place of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A305-(2-Fluoro-phenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 2-fluoro-phenol [Aldrich]in place of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A315-(2-Ethyl-phenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 2-ethyl-phenol [Aldrich]in place of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A325-(2-,5-Difluorophenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 2,5-difluorophenol[Aldrich] in place of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A335-(2-Trifluoromethylphenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 2-trifluoromethylphenol[Aldrich] in place of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A345-(2,4-Difluorophenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 2,4-difluorophenol[Aldrich] in place of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A355-(4-Fluoro-2-methoxyphenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 4-fluoro-2-methoxyphenol[Aldrich] in place of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A365-(2-Methoxyphenoxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the method of Example A15 but utilising 2-methoxyphenol [Aldrich]in place of 4-chlorophenol to give the title compound as thetrifluoroacetate salt.

EXAMPLE A375-(Cyclohex-2-enyloxy)-2-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]isoindol-1,3-dione

Using the procedure of Example A39 but utilising racemic 2-cyclohexenol[Aldrich] in place of 3-methyl-2-butenol to give first4-(cyclohex-2-enyloxy)-phthalic acid dimethyl ester;

¹H NMR (CDCl₃): δ 1.60-2.20 (m, 6H), 3.86 (s, 3H), 3.90 (s, 3H),4.85-4.90 (m, 1H), 5.81-5.85 (m, 1H), 5.98-6.02 (m, 1H), 6.99 (d, J 8.8,1H), 7.07 (s, 1H), 7.79 (d, J 8.8, 1H).

This was progressed in the same manner as4-(3-methylbut-2-enyloxy)phthalic acid dimethyl ester in the sameexample to give the title compound as the hydrochloride salt, aracemate.

EXAMPLE A382-[3-Methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-5-(pent-2-enyloxy)isoindol-1,3-dione

Using the procedure of Example A39 but utilising a 2.7:1 mixture of Zand E-pent-2-enol [Aldrich] in place of 3-methyl-2-butenol to give thetitle compound as a 2.7:1 mixture of Z and E isomers as theirhydrochloride salts

EXAMPLE A392-[3-Methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-5-(3-methylbut-2-enyloxy)isoindol-1,3-dione

3-Methyl-2-butenol [Aldrich] was used in place of allyl alcohol in theprocedure described in Angew. Chem., 1992, 104, 198-200, to prepare4-allyloxyphthalic acid dimethyl ester. This gave4-(3-methylbut-2-enyloxy)phthalic acid dimethyl ester; ¹H NMR (CDCl₃): δ1.74 (s, 3H), 1.80 (s, 3H), 3.86 (s, 3H), 3.91 (s, 3H), 4.56 (d, J 6.7,2H), 5.44-5.48 (m, 1H), 6.98 (d, J 8.6, 1H), 7.07 (s, 1H), 7.79 (d, J8.6, 1H). This material was treated by the same procedure used in Angew.Chem., 1992, 104, 198-200, to prepare 4-allyloxyphthalic acid from4-allyloxyphthalic acid dimethyl ester, and afforded4-(3-methylbut-2-enyloxy)phthalic acid;

¹H NMR (CD₃OD): δ 1.76 (s, 3H), 1.79 (s, 3H), 4.62 (d, J 6.8, 2H),5.44-5.47 (m, 1H), 7.05 (d, J 8.8, 1H), 7.09 (s, 1H), 7.81 (d, J 8.8,1H).

A mixture of this acid (67 mg, 0.27 mmol),3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine [Example A4] (67 mg,0.28 mmol) and N-cyclohexylcarbodiimide resin (1.69 mol. eq./g, 0.46 g,0.78 mmol) was stirred in a 50:50 mixture of DMF and dichloromethane(1.5 ml) at room temperature under argon for 16 h. The mixture wasfiltered through filter-aid and the resin washed several times withdichloromethane. The filtrate was evaporated and the crude residuepurified by flash chromatography on silica gel eluting with methanol indichloromethane to yield the title compound as a brown oil;

¹H NMR (CDCl₃): δ 1.78 (s, 3H), 1.82-1.87 (m, 7H), 2.62-2.80 (m, 4H),3.01 (t, J 6.0, 2H), 3.86 (s, 3H), 4.22 (t, J 6.4, 2H), 4.66 (d, J 6.8,2H), 5.47-5.51 (m, 1H), 6.92-7.01 (m, 3H), 7.21 (d, J 8.4, 1H), 7.40 (s,1H), 7.82 (d, J 8.4, 1H),

which was converted to the hydrochloride salt by treatment with etherealhydrogen chloride (1M).

EXAMPLE A402-[3-Methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-5-(2-methylallyloxy)isoindol-1,3-dione

Using the procedure of Example A39 but utilising 2-methyl-propenol[Aldrich] in place of 3-methyl-2-butenol to give the title compound asthe hydrochloride salt.

EXAMPLE A415-(Cyclopent-2-enyloxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the procedure of Example A39 but utilising racemic 2-cyclopentenol[Wiley] in place of 3-methyl-2-butenol to give the title compound as thehydrochloride salt, a racemate.

EXAMPLE A425-Cyclohexyloxy-2-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]isoindol-1,3-dione

4-(Cyclohex-2-enyloxy)-phthalic acid dimethyl ester [Example A37] (67mg, 0.23 mmol) was hydrogenated under an atmosphere of hydrogen at roomtemperature and pressure with 10% wet Pd/C (ca. 200 mg) in THF (5 mL)for 24 h. The catalyst was removed by filtration and the solvent wasevaporated under vacuum. The crude material was purified by flashchromatography on silica gel eluting with 0-20% MeOH in DCM to yield4-cyclohexyloxy-phthalic acid dimethyl ester as an oil. m/z (APCI+) 293(15%, [M+H]⁺), 179 (100), 261 (65).

This was used in the procedure of Example A39 in place of4-(3-methylbut-2-enyloxy)phthalic acid dimethyl ester to give the titlecompound;

¹H NMR (CDCl₃): δ 1.30-2.03 (m, 14H), 2.68-2.80 (m, 4H), 3.01 (t, 2H),3.86 (s, 3H), 4.22 (t, 2H), 4.40-4.46 (m, 1H), 6.92-7.00 (m, 3H), 7.19(d, 1H), 7.38 (s, 1H), 7.81 (d, 1H); m/z (APCI−) 463 (20%, [M−H]⁻), 381(100%).

EXAMPLE A435-(Cyclopentyloxy)-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione

Using the procedure of Example A42 but utilising racemic4-(cyclopent-2-enyloxy)-phthalic acid dimethyl ester [Example A41]inplace of 4-(cyclohex-2-enyloxy)-phthalic acid dimethyl ester to give thetitle compound as the hydrochloride salt, a racemate

EXAMPLES B1, B22-[4-(2-Diisopropylamino-ethoxy)-3-methoxy-phenyl]-5-phenyl-2,3-dihydro-isoindol-1-one2-[4-(2-Diisopropylamino-ethoxy)-3-methoxy-phenyl]-6-phenyl-2,3-dihydro-isoindol-1-one

A solution of5-bromo-2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-isoindole-1,3-dione[Example A1] (66 mg, 0.14 mmol) was dissolved in THF (ml) and treatedwith sodium borohydride (5.2 mg, 0.14 mmol). After stirring for 2 hours,the mixture was treated with isopropanol, stirred for a further 1 h thentreated with acetic acid (2 drops) and stirred for 16 h at RT. Thesolvent was removed and the residue purified by flash chromatography togive an approximately 1:1 mixture of the 5- and 6-bromo substitutedisomers of2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-3-hydroxy-2,3-dihydro-isoindol-1-one(37 mg). This material was dissolved in dichloromethane (2 ml) andtreated with triethylsilane (1 ml) and trifluoroacetic acid (0.5 ml).The mixture was stirred at RT for 16 hours, the solvents were removed invacuo and the residue purified by flash chromatography on silica gel(eluting with methanol-dichloromethane-aq. ammonia) to obtain2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-isoindol-1-oneas an approximately 1:1 mixture of 5- and 6-bromo isomers (33 mg). Asolution of this material in benzene (5 ml) was treated with aqueoussodium carbonate (2M, 1 ml), ethanol (1 ml), phenylboronic acid (9 mg,0.07 mmol) and tetrakis(triphenylphosphine)palladium[0] (10 mg) and themixture heated to reflux for 16 h. The less dense phase was decanted,filtered through filter-aid (washing with dichloromethane), the filtrateevaporated and purified by flash chromatography on silica gel (elutingwith dichloromethane-methanol-aq. ammonia) and reverse phase preparativechromatography (aq. MeCN, TFA) to give the title compounds as anapproximately 1:1 mixture of isomers as their TFA salts;

¹H NMR (CDCl₃): δ 1.5 (bd, 12H), 3.47 (d, 2H), 3.82 (m, 2H), 3.93 (s,3H), 4.5 (t, 2H), 4.88, 4.89 (2s, 2H), 6.94-7.05 (2H, m), 7.25-7.75 (7H,m), 7.84 (0.5H, dd), 7.96 (0.5H, dd), 8.08-8.17 (1H, m), 12.5 (1H, bs)(m/z AP+) 459.

EXAMPLE B32-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-phenoxy-2,3-dihydro-isoindol-1-one

Utilising the procedure outlined in Example B1/B2 but with2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-phenoxy-isoindole-1,3-dione[Example A4] in place of5-bromo-2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-isoindole-1,3-dionegave the title compound in place of5/6-bromo-2-[4-(2-diisopropylamino-ethoxy)-3-methoxy-phenyl]-2,3-dihydro-isoindol-1-one,but as the single isomer, as a TFA salt:

¹H NMR (CDCl₃): δ 2.1 (bd, 4H), 3.1 (2H, bm), 3.5 (2H, bs), 3.89 (s,3H), 3.9 (bs, 2H), 4.43 (2H, bs), 4.7 (s, 2H), 6.90-7.44 (m, 9H), 7.93(d, 1H), 7.94 (d, 1H), 12.5 (bs 1H).

EXAMPLE C13-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-7-phenoxy-3H-benzo[d][1,2,3]triazin-4-one

A solution of 2,4-dinitrobenzoic acid [Aldrich](1.06 g, 5 mmol) indichloromethane (20 ml) was treated with oxalyl chloride (2 ml) and 1drop DMF. Vigorous evolution of gas occurred which ceased after 1 hour.The solution was evaporated to the yellow acid chloride. A solution ofphenol (1.5 g, 15.5 mmol) in DMF (20 ml) was introduced into a secondflask charged with sodium hydride (480 mg, 60% oil dispersion, 12 mmol).When all the hydride had dissolved this solution was treated with theacid chloride, portionwise over five minutes. The solution was thenheated to 60° C. for 12 h, cooled, the solvents removed by evaporationin vacuo, and the residue treated with a solution of 40% sodiumhydroxide (50 ml) and ethanol (50 ml). The mixture was stirred at RT for12 hours then acidified to pH 2 with (2M aq HCl) and extracted intoethyl acetate (3×100 ml). The combined organic phase was washed withsaturated brine (50 ml), dried (MgSO₄), filtered, and evaporated to ayellow solid. This was purified by flash chromatography (ethylacetate-hexane) to give 2-nitro-4-phenoxy-benzoic acid (894 mg, 69%);

¹H NMR (CDCl₃): δ 4.8 (1H, bs), 7.10 (1H, dd), 7.16 (1H, dd), 7.21 (1H,d), 7.26-7.31 (2H, m), 7.46 (2H, dd), 7.94, (1H, d).

This acid (445 mg, 1.72 mmol) was dissolved in dichloromethane (10 ml)and treated with oxalyl chloride (2 ml) and 1 drop of DMF. Vigorousevolution of gas occurred which ceased after 1 hour. The solution wasevaporated to the yellow acid chloride. This was dissolved indichloromethane (10 ml) and treated with3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine [Example A4] anddiethylisopropylamine polystyrene resin beads (3.49 mol. eq./g, 0.6 g).The mixture was shaken for 12 hours then filtered, evaporated andpurified by flash chromatography on silica gel (eluting withammonia-methanol-dichloromethane) to giveN-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-nitro-4-phenoxy-benzamideas a yellow foam (600 mg, 73%);

¹H NMR (CDCl₃): δ 1.81 (4H, m), 2.64 (4H, m), 2.94 (2H, t), 3.84 (3H,s), 4.14 (2H, t), 6.84 (1H, d), 6.93 (1H, dd), 7.08 (2H, d), 7.22-7.47(5H, m), 7.56-7.60 (2H, m), 7.80 (1H, bs); m/z [AP+] 478 (M+H⁺, 100%).

This amine (400 mg, 0.83 mmol) was dissolved in ethanol (40 ml) andtreated with 10% palladium on carbon (250 mg), then the mixture washydrogenated at atmospheric pressure for 18 hours. The mixture wasfiltered and the solvent removed in vacuo to give2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamideas a cream solid (380 mg, 100%);

¹H NMR (CDCl₃): δ 1.99 (4H, bs), 3.14 (4H, bs), 3.24 (2H, t), 3.82 (3H,s), 4.30 (2H, t), 5.58 (2H, bs), 6.22 (1H, d), 6.30 (1H, dd), 6.81 (1H,d), 6.98 (1H, dd), 7.04 (2H, d), 7.15 (1H,t), 7.34-7.42 (3H, m), 7.57(1H, d), 8.21 (1H, bs); m/z [AP+] 459 (M+H⁺, 100%).

This amine (58 mg, 0.13 mmol) was dissolved in dichloromethane (5 ml)and acidified with trifluoroacetic acid (200 ul) then treated with butylnitrite [Aldrich](0.1 ml); a brown colour immediately appeared. After 1minute, the mixture was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene(DBU) [Aldrich] (0.5 ml). The colour immediately faded. The solvent wasremoved and the residue purified by flash chromatography using silicagel (eluting with dichloromethane-methanol-ammonia) to give the titlecompound;

¹H NMR (CDCl₃): δ 1.83 (4H, m), 2.69 (4H, m), 3.01 (2H, t), 3.90 (3H,m), 4.24 (2H, t), 7.03 (1H, d), 7.14-7.18 (4H, m), 7.30 (1H, t),7.50-7.54 (4H, m), 8.39 (1H, d)

which was crystallized from ether-HCl as the hydrochloride salt, a paleyellow solid

EXAMPLE C23-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-7-phenoxy-3H-quinazolin-4-one

2-Amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamide[Example C1] (50 mg, 0.11 mmol) was dissolved in 1,2-dichloroethane (5ml) and treated with triethylorthoformate [Aldrich] (2 ml) then heatedto reflux for 12 h. The mixture was cooled and DBU (0.1 ml) introduced.The solvent was evaporated then the residue purified by flashchromatography on silica gel (eluting withammonia-methanol-dichloromethane) to obtain the title compound;

¹H NMR (CDCl₃): δ 1.86 (4H, m), 2.69 (4H, m), 3.02 (2H, t), 3.88 (3H,t), 4.24 (2H, t), 6.89-6.93 (2H, m), 7.01 (1H,d), 7.12-7.26 (5H, m),7.43 (2H, t), 8.07 (1H, s), 8.31 (1H, dd); which was crystallized fromether-HCl as the hydrochloride salt, a white solid.

EXAMPLE C33-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-7-phenoxy-1H-quinazoline-2,4-dione

2-Amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamide[Example C1] (62 mg, 0.14 mmol) was dissolved in dichloromethane (5 ml)and treated with carbonyl diimidazole (50 mg, 0.31 mmol) and DBU (0.1ml). The mixture was stirred for 4 h at RT then the solvent removed andthe residue purified by flash chromatography on silica gel (eluting withammonia-methanol-dichloromethane) to obtain the title compound;

¹H NMR (CDCl₃): δ 1.79 (4H, m), 2.64 (4H, m), 2.97 (2H, t), 3.82 (3H,s), 4.20 (2H, t), 6.46 (1H, d), 6.76-6.83 (3H, m), 6.98 (1H, d), 7.09(2H, d), 7.23-7.27 (1H, m), 7.40-7.44 (2H, m), 8.08 (1H, d), 8.8 (1H,bs);

which was crystallized from ether-HCl as the hydrochloride salt, a whitesolid.

EXAMPLE C43-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-methyl-7-phenoxy-3H-quinazolin-4-one

2-Amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamide[Example C1] (50 mg, 0.11 mmol) was dissolved in 1,2-dichloroethane (5ml) and treated with triethylorthoacetate [Aldrich] (2 ml) then heatedto 100° C. for 12 h. The mixture was cooled and DBU (0.1 ml) introduced.The solvent was evaporated then the residue purified by flashchromatography on silica gel (eluting with aq.ammonia-methanol-dichloromethane) to obtain the title compound as awhite solid;

¹H NMR (CDCl₃): δ 1.82 (4H, m), 2.23 (3H, s), 2.67 (4H, m), 3.00 (2H,t), 3.86 (3H, s), 4.22 (2H, t), 6.72 (1H, d), 6.77 (1H, dd), 7.00-7.04(2H, m), 7.12-7.22 (3H, m), 7.26 (1H, t), 7.42 (2H, t), 8.22 (1H, d).

EXAMPLE C53-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-7-phenyl-3H-benzo[d][1,2,3]triazin-4-one

3-Nitrobiphenyl (3.0 g, 15 mmol), was dissolved in DMF (7.5 ml) and drychloroform (16.5 mmol). This mixture was added dropwise to a stirredprecooled mixture of potassium tert-butoxide (7.2 mg, 60 mmol) in DMF(20 ml) and THF (25 ml), at such a rate that the temperature wasmaintained between −69 and −73° C. When the addition was complete, themixture was stirred for a further 1 minute then treated with acetic acid(1.5 ml) in methanol (5 ml) and allowed to warm to room temperature. Themixture was treated with saturated aqueous sodium bicarbonate (50 ml)and extracted with dichloromethane (3×50 ml), the combined organic phasedried (MgSO₄), filtered and evaporated, then the residue purified byflash chromatography (ether-hexane). This gave a yellow material whichconsisted of between 30 and 50% of dichloromethyl substituted3-nitrobiphenyl and starting material. The mixture was dissolved inacetonitrile (10 ml) and treated with a solution of silvertrifluoromethanesulphonate (15 mmol, 3.84 g) in water (5 ml). Themixture was heated to reflux for 16 h in the dark then cooled, themixture concentrated in vacuo, filtered and the filtrate extracted withether (3×50 ml). The combined organic phase was evaporated and purifiedby flash chromatography to give 3-nitrobiphenyl-4-carbaldehyde;

¹H NMR (CDCl₃): δ 7.51-7.58 (3H, m), 7.29 (3H, s), 7.51-7.58 (3H, m),7.69 (2H, dd), 8.03, 8.08 (2H, 2×d), 8.34 (1H, d), 10.49 (1H, s).

This aldehyde (454 mg, 2.0 mmol) was dissolved in acetic acid (10 ml)and treated with sodium perborate tetrahydrate (385 mg, 2.5 mmol), themixture was heated to 50° C. for 48 h then cooled, concentrated to apaste and washed with water (2×50 ml). The residue was dried in adesiccator to afford 3-nitrobiphenyl-4-carboxylic acid as a white solid(420 mg, 87%);

¹H NMR (CDCl₃): δ 5.5 (1H, bs), 7.48-7.56 (4H, m), 7.30 (1H, bs),7.50-7.77 (3H, m).

This acid (417 g, 1.72 mmol) was dissolved in dichloromethane (10 ml)and treated with oxalyl chloride (2 ml) and 1 drop of DMF. Vigorousevolution of gas occurred which ceased after 1 hour. The solution wasevaporated to the yellow acid chloride. This was dissolved indichloromethene (10 ml) and treated with3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine [Example C1] (472 mg,2 mmol) and diethylisopropylamine polystyrene resin beads (1.0 g, 3.6mmol equiv). The mixture was shaken for 12 hours then filtered,evaporated and purified by flash chromatography on silica gel (elutingwith ammonia-methanol-dichloromethane) to giveN-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-nitro-4-phenyl-benzamideas a yellow foam (563 mg, 71%);

¹H NMR (CDCl₃): δ 1.78 (4H, bs), 2.61 (4H, bs), 2.91 (2H, t), 3.79 (3H,s), 4.10 (2H, t), 6.80 (1H, d), 6.98 (1H, dd), 7.32 (1H, d), 7.42-7.50(3H, m), 7.57 (2H, d), 7.66 (1H, d), 7.83 (1H, dd), 8.20 (2H, dd). m/z[AP+] 462 (M+H⁺, 100%).

This amine (560 mg, 1.3 mmol) was dissolved in ethanol (20 ml) andtreated with 10% palladium on carbon (100 mg) then the mixturehydrogenated at atmospheric pressure for six hours. The mixture wasfiltered and the solvent removed in vacuo to give2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenyl-benzamideas a cream solid (518 mg, 99%);

¹H NMR (CDCl₃): δ 1.82 (4H, m), 2.68 (4H, m), 2.96 (2H, t), 3.86 (3H,s), 4.16 (2H, t), 5.6 (2H, bs), 6.86-6.97 (4H, m), 7.35-7.58 (7H, m),7.89 (1H, bs). m/z [AP+] 431(M+H⁺ 100%).

This amine was treated in the manner of2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamidein Example C1 to give the title compound;

¹H NMR (CDCl₃): δ 1.86 (4H, m), 2.73 (4H, m), 3.05 (2H, t), 3.91 (3H,t), 4.29 (2H, t), 7.06 (1H, d), 7.18-7.24 (2H, m), 7.47-7.57 (3H, m),7.76 (2H, d), 8.06 (1H, d), 8.42 (1H, d), 8.49 (1H, d).

which crystallised from Et₂O/HCl as a pale yellow solid.

EXAMPLE C63-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-7-phenyl-3H-quinazolin-4-one

Using2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenyl-benzamide[Example C5] in the manner of2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamidein Example C2, gave the title compound as a cream solid;

¹H NMR (CDCl₃): δ 1.83 (4H, m), 2.69 (4H, m), 3.01 (2H, t), 3.90 (3H,t), 4.24 (2H, t), 6.92-6.96 (2H, m), 7.03 (1H, d), 7.43-7.53 (3H, m),7.72 (2H, d), 7.79 (1H, dd), 7.98 (1H, d), 8.15 (1H, s), 8.42 (1H,d).

EXAMPLE C73-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-7-phenyl-1H-quinazoline-2,4-dione

Using2-Amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenyl-benzamide[Example C5] in the manner of2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamidein Example C3, gave the title compound;

¹H NMR (CDCl₃): δ 1.82 (4H, m), 2.67 (4H, m), 2.99 (2H, t), 3.83 (3H,s), 4.21 (2H, t), 6.81 (1H, d), 6.85 (1H, dd), 7.00 (1H, d), 7.23 (1H,d), 7.45-7.52 (4H, m), 7.62 (2H, d), 7.66 (1H, s), 8.21 (1H, d);

which crystallised from diethyl ether/HCl as a cream solid.

EXAMPLE C83-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-methyl-7-phenoxy-3H-quinazolin-4-one

Using2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenyl-benzamide[Example C5] in the manner of2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamidein Example C4, gave the title compound;

¹H NMR (CDCl₃): δ 1.85 (4H, m), 2.31 (3H, s), 2.69 (4H, m), 3.02 (2H,t), 3.87 (3H, t), 4.24 (2H, t), 6.76 (1H, d), 6.83 (1H, dd), 7.04 (1H,d), 7.41-7.52 (3H, m), 7.70-7.91 (3H, m), 7.91 (1H, d), 8.32 (1H, d).

EXAMPLE C97-Allyloxy-3-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-3H-quinazolin-4-onehydrochloride

4-allyloxy-2-nitro-benzoic acid allyl ester [J. Org. Chem. 1987, 52(18),4086] (0.21 g, 0.8 mmol) was dissolved in ethanol (5 ml), and 40% sodiumhydroxide added (5 ml). The mixture was stirred for 16 h then acidifiedto pH 2 with 2M hydrochloric acid. The mixture was extracted with ethylacetate (3×25 ml) and the combined organic phases washed with brine (75ml), dried (M_(g)SO₄) and concentrated to yield4-allyloxy-2-nitrobenzoic acid as brown solid (0.16 g);

¹H-NMR (DMSO) δ 4.72-4.74 (m, 2H), 5.29-5.45 (dd, 2H), 5.99-6.07 (m,1H), 7.28-7.31 (dd, 1H), 7.49-7.50(d, 1H), 7.82-7.87 (d, 1H) 13.45 (bs,1H).

This acid (0.16 g, 0.72 mmol) was dissolved in dichloromethane (1 ml)and oxalyl chloride (0.2 ml) added, followed by 1 drop of DMF. Themixture was stirred under argon for 1 hr and concentrated to yield4-allyloxy-2-nitrobenzoyl chloride, an orange solid (0.173 g). This wasredissolved in dichloromethane (5 ml) and added dropwise to a stirredsolution of 3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine [ExampleC1] (154 mg, 0.66 mmol) and triethylamine (72.8 mg, 0.72 mmol) in 5 mldichloromethane. The mixture was stirred for 90 minutes, then thesolution washed with saturated sodium hydrogen carbonate (25 ml), andbrine (25 ml). The residue was dried (MgSO₄) and concentrated to yield4-allyloxy-N-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-2-nitro-benzamidea brown solid (191.5 mg);

¹H-NMR (CDCl₃) δ 1.93 (bs, 4H), 3.04 (bm, 4H), 2.80-2.81 (bm, 2H), 3.74(s, 3H), 4.21 (bm, 2H), 4.61-4.63 (bd, 2H), 5.30-5.47 (dd, 2H),5.98-6.08(m, 1H), 6.75-6.77 (d, 1H), 6.96-6.99 (dm, 1H), 7.14-7.17 (dm,1H), 7.49-7.50 (d, 2H), 7.57-7.59 (d, 1H), 8.59 (s, 1H).

A solution of this material (191.5 mg, 0.43 mmol) in methanol was addeddropwise to a stirred suspension of iron powder (72.6 mg, 1.3 mmol) andammonium chloride (115.8 mg, 2.17 mmol) in water (5 ml). The mixture washeated to 80° C. for 90 mins, then hot filtered through celite. Thefilter cake was washed with dichloromethane (10 ml) and water (10 ml).The organic phase was separated and the aqueous layer basified withsaturated sodium hydrogen carbonate. The aqueous layer was extractedwith dichloromethane (3×10 ml) and the combined organic layers washedwith brine (10 ml), then dried (MgSO₄) and concentrated to yield4-allyloxy-2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-benzamideas a yellow gum;

¹H-NMR (DMSO) 61.76-1.82 (bm, 4H), 2.62-2.64 (bm, 4H), 2.92-2.85 (t,2H), 3.85 (s, 3H), 4.12-4.16 (t, 2H), 4.51-4.53 (m, 2H), 5.28-5.42 (m,2H), 5.63 (bs, 2H), 5.99-6.06 (m, 1H), 6.18-6.19 (d, 1H), 6.26-6.29 (dd,1H), 6.85-6.91 (m, 3H), 7.29-7.38 (d, 1H), 7.62 (s, 1H).

This material was treated in the same manner as2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamide[Example C1] in the method of Example C2 to afford7-allyloxy-3-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-3H-quinazolin-4-onewhich was crystallised from ether-HCl to give the title compound as ayellow solid (21.5 mg);

¹H-NMR (CDCl₃) δ 2.11-2.25 (bd, 4H), 3.06 (bs, 2H), 3.54-3.57 (bd, 2H),3.88 (bs, 5H), 4.62 (bs, 2H), 4.69-4.72 (dm, 2H), 5.35-5.53 (dd, 2H),6.03-6.10 (m, 1H), 6.96 (bs, 2H), 7.07-7.10 (d, 1H), 7.17-7.21 (dd, 1H),7.31-7.32 (d, 1H), 8.23-8.27 (d, 1H), 8.36 (s, 1H), 12.85 (bs, 1H).

EXAMPLE D13-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-phenoxy-3H-benzo[d][1,2,3]triazin-4-one

5-Chloro-2-nitrobenzoic acid [Aldrich] (600 mg, 3 mmol) was suspended indichloromethane (5 ml) and treated with oxalyl chloride (2 ml) and DMF(1 drop). On stirring, an immediate effervescence occurred which ceasedafter 1 hour. The solvent was removed in vacuo and the residue dissolvedin dichloromethane (10 ml) and treated successively with DIEA resin (3.1mmol/g, 1.95 g) and 3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine(650 mg, 3 mmol). The mixture was stirred at RT for 16 hours thenfiltered, evaporated, and the residue purified by flash chromatography(methanol-dichloromethane-aqueous ammonia) to afford5-chloro-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-nitro-benzamideas a yellow foam;

¹H NMR (CDCl₃): δ 1.86 (4H, m), 2.68 (4H, m), 2.98 (2H, t), 3.87 (3H,s), 4.16 (2H, t), 6.87 (1H, d), 6.94 (1H, dd), 7.34 (1H, d), 7.56-7.64(3H, m), 8.09 (1H, d); m/z [AP+] 420 (100%, (M+H⁺), 422.

A solution of this material (210 mg, 0.5 mmol) in DMF (2 ml) was treatedwith phenol (94 mg, 1 mmol) and sodium hydride (60% oil dispersion, 36mg, 0.9 mmol) then the mixture heated to 60° C. for 48 h. The solutionwas cooled, evaporated and the residue suspended in dichloromethane andfiltered. The filtrate was evaporated and purified by flashchromatography on silica gel (eluting withmethanol-dichloromethane-aqueous ammonia) to affordN-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-nitro-5-phenoxy-benzamide(200 mg, 84%) as a yellow wax;

¹H NMR (CDCl₃): δ 1.80 (4H, m), 2.62 (4H, m), 2.92 (2H, t), 3.82 (3H,s), 4.12 (2H, t), 6.83 (1H, d), 6.93 (1H, dd), 7.03-7.11 (4H, m),7.26-7.41 (2H, m), 7.43 (2H, m), 7.77 (1H, m), 8.11 (1H, d) m/z [AP+]420 (100% M+H⁺).

A solution of this amine (100 mg, 0.24 mmol) in ethanol (10 ml) wastreated with 10% palladium on carbon (50% wet, 100 mg), and hydrogenatedat RT for 12 hours. The mixture was filtered, and the solvent removed invacuo to give2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-phenoxy-benzamideas a white waxy solid, a portion of which was crystallised from Et₂O/HClto give the hydrochloride salt

¹H NMR (CDCl₃): δ 1.99-2.11 (6H, bm), 2.97 (2H, bs), 3.39 (2H, bs), 3.77(3H, s), 4.38 (2H, bs), 5.5 (2H, bs), 6.66 (1H, d), 6.78-6.98 (6H, m),7.20-7.24 (1H, m), 7.36 (1H, s), 8.06 (1H, brs), 12.5 (1H, brs) m/z[AP+] 448 (100%, M+H⁺).

A solution of the free base of this amine (58 mg, 0.13 mmol) indichloromethane (2 ml) was acidified with 5 drops of TFA then treatedwith butyl nitrite (100 ul). A deep orange colour formed immediately.After 1 minute, DBU was introduced dropwise until basic. The solvent wasremoved in vacuo and the residue purified by flash chromatography onsilica gel (eluting with methanol-dichloromethane-aqueous ammonia) togive the title compound which crystallised as a pale yellow HCl salt ontreatment with 1M HCl in ether;

¹H NMR (CDCl₃): δ 2.11, 2.25 (4H, 2×m), 3.07 (2H, m), 3.53 (2H, m), 3.88(3H, s), 3.92 (2H, m), 4.61 (2H, t), 7.08 (1H, d), 7.12 (2H, d),7.16-7.27 (2H, m), 7.45 (2H, t), 7.64 (1H, dd), 7.76 (1H, d), 8.20(1H,d), 12.9 (1H, bs).

EXAMPLE D23-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-phenoxy-3H-quinazolin-4-one

A solution of2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-phenoxy-benzamide[Example D1] (25 mg, 0.055 mmol) in 1,2-dichloroethane (1 ml) wastreated with triethylorthoformate (2 ml) and the mixture heated to 80°C. for 16 hours. The mixture was cooled, 1 drop of DBU added and themixture evaporated. The residue was subjected to flash chromatography onsilica gel eluting with (methanol-dichloromethane-aqueous ammonia) togive the title compound;

¹H NMR (CDCl₃): δ 1.83 (4H, m), 2.67 (4H, m), 2.99 (2H, t), 3.88 (3H,s), 4.22 (2H, t), 6.89-6.92 (2H, m), 7.01 (1H, d), 7.08 (2H, d), 7.17(1H, t), 7.38 (2H, t), 7.53 (1H, dd), 7.76 (1H, d), 7.84 (1H, d), 8.05(1H, s); which crystallised as a pale yellow HCl salt on treatment with1M HCl in ether.

EXAMPLE D33-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-phenoxy-1H-quinazoline-2,4-dione

A solution of2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-phenoxy-benzamide[Example D1] (25 mg, 0.055 mmol) in dichloromethane (1 ml) was treatedwith carbonyl diimidazole (16 mg, 0.1 mmol), and DBU (1 drop). Themixture was stirred at RT for 4 hours then evaporated and the residuepurified by flash chromatography on silica gel (eluting withmethanol-dichloromethane-aqueous ammonia) to give the title compound;

¹H NMR (CDCl₃): δ 1.84 (4H, m), 2.0 (1H, brs), 2.74 (4H, m), 3.03 (2H,t), 3.82 (3H, s), 4.23 (2H, t), 6.77-6.84 (2H, m), 6.98-7.03 (4H, m),7.12 (1H, t), 7.31-7.36 (3H, m), 7.71 (1H, d); which crystallised as awhite HCl salt on treatment with 1M HCl in ether.

EXAMPLE D43-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-2-methyl-6-phenoxy-3H-quinazolin-4-one

A solution of2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-phenoxy-benzamide[Example D1] (25 mg, 0.055 mmol) in 1,2-dichloroethane (1 ml) wastreated with triethylorthoacetate (2 ml) and the mixture heated to 80°C. for 2 hours. The mixture was cooled, 1 drop of DBU added and themixture evaporated. The residue was subjected to flash chromatography onsilica gel eluting with (methanol-dichloromethane-aqueous ammonia) togive the title compound;

¹H NMR (CDCl₃): δ 1.83 (4H, m), 2.27 (3H, s), 2.69 (4H, m), 3.01 (2H,t), 3.86 (3H, s), 4.23 (2H, t), 6.72 (1H, d), 6.77 (1H, dd), 7.00-7.06(3H, m), 7.14 (1H, t), 7.36 (2H, dd), 7.48 (1H, dd), 7.67 (1H, d), 7.77(1H, d); which crystallised as a white HCl salt on treatment with 1M HClin ether.

EXAMPLE D56-(4-Chloro-phenyl)-3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-quinazolin-4-one

4′-Chloro-4-nitro-biphenyl [J. Amer. Chem. Soc; 68; 1946; 404] (2.74 g,11.7 mmol) was dissolved in DMF (20 ml) and THF (6 ml), then potassiumt-butoxide 5.26 g (47 mmol) was added. The stirred mixture was cooled to−73° C. then a solution of chloroform in THF (6 ml) was slowlyintroduced, maintaining this temperature. After a further 1 minute, thereaction was quenched with acetic acid (5 ml). The mixture was pouredinto water (200 ml) and extracted with dichloromethane. The crudeproduct was purified by flash chromatography on silica (usingdichloromethane-hexane as eluents) to give4′-chloro-3-(1,1-dichloro-methyl)-4-nitro-biphenyl in 63% yield;

¹H NMR (CDCl₃): δ 8.33 (s) 1H, 8.10 (d) 1H, 7.7 (d) 1H, 7.68 (s) 1H,7.55 (d) 2H; 7.50 (d) 2H.

4′-Chloro-3-(1,1-dichloromethyl)-4-nitrobiphenyl (0.4 g, 1.26 mmol) wasdissolved in methanolic sodium methoxide (15 mL; 0.5 M). The mixture wasrefluxed for 12 hours under argon. The solvent was evaporated and theresidue diluted in 1,4-dioxane (15 ml) and water (1 ml), then a fewdrops of concentrated HCl were added. The reaction mixture was stirredat 100° C. for 4 hours. The solvent was then evaporated and the crudemixture purified by flash chromatography on silica gel (eluting withdichloromethane in petroleum ether) to yield the4′-chloro-4-nitrobiphenyl-3-carbaldehyde (0.32 g, 1.26 mmol); m/z(APCI−) 260 (40%, [M−H]⁻), 231 (100%). This aldehyde (0.32 g, 1.26 mmol)was dissolved in acetic acid (5 mL) and sodium perborate (0.23 g, 1.5mmol) was added. The resulting mixture was stirred at 50° C. for 16 h.The mixture was cooled, the solvent was evaporated, ethyl acetate wasadded and the organic layer washed with water, dried over MgSO₄ andevaporated to yield the 4′-chloro-4-nitrobiphenyl-3-carboxylic acid(0.14 g, 41%); m/z [APCI−] 276 (100%, [M−H⁻], 247 (60%).

This acid (0.14 g, 0.5 mmol) was dissolved in dichloromethane (2 ml) andoxalyl chloride added (87 μl, 1 mmol). The mixture was stirred for 60min at room temperature under argon. The solvent was evaporated and theresidue added to a solution of3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenylamine [Example A4] (0.10 g,0.44 mmol) and triethylamine (70 μl, 0.5 mmol) in dichloromethane (4ml). The mixture was stirred for 90 mins at room temperature under argonand then washed with a saturated aqueous solution of NaHCO₃ (5 ml) andbrine (5 ml). The organic layer was dried over MgSO₄, the solventevaporated and the residue purified by flash chromatography on silicagel (eluting with methanol-dichloromethane-aq. ammonia).4′-Chloro-4-nitrobiphenyl-3-carboxylic acid[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]amide was obtained in 54%yield; m/z [APCI⁺] 496 (100%, M+H⁺). Iron powder (45 mg, 0.81 mmol) andammonium chloride (72 mg, 1.35 mmol) were mixed in water (2 ml) and4′-chloro-4-nitrobiphenyl-3-carboxylic acid[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]amide (0.13 g, 0.27 mmol)added, dissolved in MeOH (2 ml). The mixture was heated at 80° C. for 90min and then filtered while hot. Dichloromethane (30 ml) was added tothe cooled filtrate. The organic layer was washed with water (10 ml),saturated aqueous NaHCO₃ (10 ml) and brine (10 ml), then dried and thesolvent evaporated to give a yellow gum. This was dissolved in1,2-dichloroethane (10 ml) and triethylorthoformate (4 ml). The mixturewas refluxed for 16 h under argon, then after cooling DBU (0.2 ml) wasadded and the mixture was stirred for 10 mins at room temperature. Thesolvent was evaporated and the residue purified by flash chromatographyon silica gel (eluting with methanol-dichloromethane-aqueous ammonia) toyield the title compound as an orange gum;

¹H NMR (CDCl₃): δ 1.78-1.86 (m, 4H), 2.65-2.78 (m, 4H), 2.99 (t, 2H),3.89 (s, 3H), 4.22 (t, 2H), 6.92-6.95 (m, 2H), 7.03 (d, 1H), 7.45 (d,2H), 7.63 (d, 2H), 7.83 (d, 1H), 8.00 (d, 1H), 8.13 (s, 1H), 8.54 (s,1H);

which was converted to the hydrochloride salt by treatment with asolution of HCl in ether.

EXAMPLE E13-[3-Methoxy-4-(2-pyrrolidin-yl-ethoxy)-phenyl]-6-phenyl-3H-thieno[2,3-d]1triazine-4-one

6-Phenyl-3H-thieno[2,3-d][1,2,3]-triazinone (Indian Journal ofChemistry, 9, 1971, 1209), (100 mg, 0.44 mmol) and3-methoxy(4-pyrrolidin-1-ylethoxy)phenylamine (103 mg, 0.44 mMol)[Example A4] were refluxed in xylene (5 ml) for 16 h. The solvent wasevaporated and the residue purified by chromatography on deactivatedneutral alumina (eluting with ethyl acetate-methanol) to give2-amino-5-phenyl-thiophene-3-carboxylic acid[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amide in 38% yield;

¹H NMR (CDCl₃): δ 10.7 (bs, 1H), 9.4 (s, 1H), 7.90 (s, 1H), 7.62 (s,2H), 7.51 (d, 1H), 7.48 (d, 2H), 7.39 (t, 2H), 7.3 (dd, 1H), 7.18 (t,1H), 7.01 (d, 1H), 4.29 (t, 2H), 3.80 (s, 3H), 3.51 (m, 4H), 1.98 (m,4H); m/z [ES+], 438, [ES−] 436.

This material (50 mg, 0.114 mmol) was treated with butyl nitrite (1 ml)in dichlomethane (5 ml) at room temperature. The crude product waspurified by flash chromatography on silica gel (eluting withdichloromethane-methanol-aq. ammonia) to give the title compound;

¹HNMR(CDCl₃): δ 7.87 (s, 1H), 7.75 (d, 2H), 7.49 (m, 3H), 7.18 (dd, 1H),7.15 (dd, 1H), 7.05 (d, 1H), 4.26 (t, 2H), 3.91 (s, 3H), 3.01 (t, 2H),3.67 (m, 4H), 1.82 4H.

EXAMPLE E23-[3-Methoxy-4-(2-pyrrolidin-yl-ethoxy)-phenyl]-6-phenyl-3-H-thieno-[2,3-d]pyrimidin-4-one

2-Amino-5-phenyl-thiophene-3-carboxylic acid[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-amide [Example E1] (28mg, 0.064 mmol) was stirred at 95° C. in triethyl orthoformate (5 ml)for 24 h. The mixture was cooled, 4 drops of DBU added and the volatilesremoved. The crude product was purified by chromatography on silica gel(eluting with dichloromethane-methanol-aq. ammonia) to give the titlecompound.

¹H NMR (CDCl₃): δ 8.06 (s, 1H), 7.73 (s, 1H) 7.68 (d, 2H) 7.42 (t, 3H),7.35 (t, 1H), 7.01 (d, 1H), 6.92 (s, 1H) 4.23 (t, 2H), 3.92 (s, 3H),3.00 (t, 2H), 2.68 (m, 4H), 1.84 (m, 4H).

EXAMPLE F13-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-6-phenyl-3H-thieno[3,2-d]pyrimidin-4-one

A solution of3-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-2-(methylthio)-6-phenylthieno[3,2-d]pyrimidin-4(3H)-one[Example F2] 80 mg (0.16 mmol) in ethanol (10 ml) was treated with RaneyNickel [W10, 50 mg] with stirring at room temperature for 1 h. Thesolvent was evaporated and the residue purified by reverse phasepreparative chromatography (using acetonitrile-water-TFA) to give thetitle compound as a trifluoroacetate salt;

¹H NMR (CDCl₃): δ 8.25 (bs, 1H), 7.76 (d, 2H), 7.61 (m, 2H), 7.50 (m,3H), 7.05 (d,1H), 6.98 (d,1H), 6.94 (dd, 1H), 4.46 (t, 2H), 4.00 (m,2H), 3.89 (s, 3H), 3.64 (t, 2H), 3.12 (m, 2H) 2.18 (m, 4H) 448

EXAMPLE F23-[3-methoxy-4-(2-pyrrolidin-1-ylethoxy)phenyl]-2-(methylthio)-6-phenylthieno[3,2-d]pyrimidin-4(3H)-one

5-Phenyl 3-amino thiophenecarboxylic acid methyl ester [Lancaster] (2 g,8.54 mMol) and 2,2′ Bis pyridyl thionate [Aldrich] (2 g, 8.54 mmol) weredissolved in dichloromethane (20 ml) then a solution of3-methoxy(4-pyrrolidin-1-ylethoxy)phenylamine [Example A4] indichloromethane (20 ml) introduced. The mixture was stirred for 2 hoursat room temperature, then the solvent removed and the product purifiedby chromatography on silica gel (eluting with methanol-dichloromethane),to give3-{3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-thioureido}-5-phenyl-thiophene-2-carboxylicacid methyl ester in 52% yield;

¹H NMR (CDCl₃): δ 10.60 (s, 1H), 9.14 (s, 1H), 7.90 (s, 1H), 7.65 (d,2H), 7.40 (m, 3H), 6.97 (d, 1H), 6.88 (m, 2H), 4.20 (t, 2H), 3.89 (s,3H), 3.73 (s, 3H), 2.98 (t, 2H), 2.66 (m, 4H), 1.83 (m, 4H). m/z 512(ES+) 510 (ES−).

This ester (300 mg, 0.56 mmol) and potassium carbonate (162 mg, 1.17mmol) were suspended in dry DMF (5 ml) and treated with a solution ofmethyl iodide (83 mg, 0.59 mmol) in DMF (1 ml). When the addition wascomplete, the mixture was evaporated. The residue was purified bychromatography on silica gel (eluting with dichloromethane-methanol)giving the title compound in 50% yield;

¹H NMR (CDCl₃): δ 7.72 (d, 2H), 7.45 (m, 4H), 7.05 (d, 1H), 6.90 (dd,1H), 6.81 (d, 1H), 4.52 (m,1H), 4.41 (m, 1H), 3.87 (s, 3H), 3.37 (m,2H), 3.21 (m, 4H), 3.52 (s, 3H), 2.08 (m, 4H).

EXAMPLE F33-[3-Methoxy-4-(pyrrolidin-1-yl-ethoxy)phenyl-6-phenyl-2-thioxo-2,3-dihydro-1H-thieno[3,2-d]pyrimidin-4-one

3-{3-[3-Methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-thioureido}-5-phenyl-thiophene-2-carboxylicacid methyl ester [Example F2] (100 mg, 0.2 mmol) was refluxed intoluene (10 ml) for 16 hours. The product was collected from the cooledsolution by filtration in 42% yield;

¹H NMR (CDCl₃): δ 7.80 (m, 2H), 7.50 (m, 4H), 7.03 (d, 1H), 6.90 (d,1H), 6.75 (dd, 1H), 4.14 (t, 2H), 3.73 (s, 3H), 2.98 (t, 2H), 2.70 (m,4H), 1.76 (m, 4H); m/z [ES+] 480; (ES−) 478.

EXAMPLE G12-[3-Methoxy-4-(3-pyrrolidin-1-yl-propyl)-phenyl]-5-phenoxy-isoindole-1,3-dione

6-Nitroindanone [J. Med. Chem., 19, 1976, 472-475] (900 mg, 5.0 mmol)was suspended in dichloromethane (25 ml) and trifluoromethanesulphonicacid (0.05 ml) added. The resulting solution was cooled on ice. In asecond flask, m-chloroperoxybenzoic acid [55%, Aldrich] (10 g) wassuspended in dichloromethane and stirred for several minutes. Theinsoluble material was removed by filtration through a hydrophobicmembrane and the filtrate evaporated to give a white powder. A portionof this material (2.6 g) was added portionwise to the indanone and theresultant suspension stirred for 72 h at room temperature. The reactionmixture was diluted with dichloromethane (10 ml) and aqueous sodiumdisulphite (20%; 10 ml). The aqueous layer was extracted (30 ml×3) withdichloromethane and the combined organic layers washed with saturatedaqueous sodium bicarbonate (20 ml), brine (10 ml), and dried (MgSO₄) toyield crude 7-nitro-chroman-2-one as a brown solid (1.1 g, ˜70% pure);

¹H NMR (CDCl₃): δ 8.01 (dd, 1H,), 7.91 (dd, 1H), 7.40 (d, 1H,), 3.14 (d,2H,), 2.86 (d, 2H,).

The crude 7-nitro-chroman-2-one (1.1 g, approx. 4.2 mmol) was dissolvedin tetrahydrofuran (15 ml). Pyrrolidine (0.35 ml) was added and thereaction mixture stirred for 1 hour. The solution was adsorbed ontosilica and eluted using methanol in dichloromethane.3-(2-hydroxy-4-nitrophenyl)-1-pyrrolidin-1-yl-propan-1-one was obtainedas a brown solid (900 mg, 3.40 mmol);

¹H NMR (CDCl₃): δ 10.62 (br, 1H); 7.74 (d, 1H); 7.66 (dd, 1H); 7.17 (d,1H); 3.47 (m, 2H); 3.36 (m, 2H); 3.00 (m, 2H); 2.70 (m, 2H); 1.92 (m,4H); MS (ES+) 265.2 (M+H⁺; 100%).

This amide (900 mg, 3.4 mmol) was dissolved in dimethylformamide (100ml) and potassium carbonate (516 mg) added, followed by iodomethane (0.6ml, 3.7 mmol). The solution was stirred for 5 hours, then concentratedin vacuo. The residual oil was partitioned between ethyl acetate (50 ml)and H₂O (50 ml), the aqueous layer extracted with ethyl acetate (3×50ml), the combined organic phases washed with brine (20 ml), dried(MgSO₄) and evaporated to yield3-(2-methoxy-4-nitrophenyl)-1-pyrrolidin-1-yl-propan-1-one as a blackoil (900 mg, 3.2 mmol);

¹H NMR (CDCl₃): δ 7.78 (dd, 1H, J=8.2 Hz, 2.2 Hz); 7.68 (d, 1H, J=2.2Hz); 7.36 (d, 1H, J=8.2 Hz); 3.93 (s, 3H); 3.46 (t, 4H, J=6.6 Hz); 3.34(t, 2H, J=7.7 Hz); 2.55 (t, 2H, J=7.7 Hz); 1.89 (m, 4H)

This amide (900 mg, 3.2 mmol) was dissolved in tetrahydrofuran (150 ml)and treated with borane:tetrahydrofuran (1M, 10 ml). The reactionmixture was heated to 50° C. for 4 hours, followed by a further additionof borane:THF solution (10 ml). After heating for a further 16 hours, athird portion (10 ml) was added, and heating maintained for a further 3hours. The reaction mixture was cooled and methanol (10 ml) added,followed by conc. hydrochloric acid (0.5 ml). The mixture was heated to80° C. for 1 hour, then evaporated in vacuo. The residue was partitionedbetween ethyl acetate (50 ml) and H₂O (50 ml), the aqueous phasesextracted with ethyl acetate (3×50 ml) and the combined organics washedwith brine (20 ml), dried (MgSO₄) and evaporated. The resultant crudebrown oil was purified by chromatography on silica gel using methanol indichloromethane as eluent.1-[3-(2-methoxy-4-nitrophenyl)-propyl]-pyrrolidine was obtained as aclear oil (186 mg, 22%);

¹H NMR (CDCl₃): δ 7.80 (dd, 1H,); 7.78 (d, 1H); 7.29 (d, 1H); 3.93 (s,3H); 3.20 (m, 2H), 2.82 (m, 2H); 2.68 (m, 4H); 2.16 (m, 4H); 1.86 (m,2H).

This amine (186 mg, 0.7 mmol) was dissolved in 4:1 mixture ofethanol:THF (20 ml), and palladium on carbon (10% wet paste; 100 mg)added. The mixture was stirred under an atmosphere of hydrogen for 16 h,then filtered over filter-aid and evaporated to yield3-methoxy-4-(3-pyrrolidin-1-yl-propyl)-phenylamine as a colourless oil(148 mg, 90%);

¹H NMR (CDCl₃): δ 6.88 (m, 1H); 6.21 (m, 2H); 3.74 (s, 3H); 3.61 (br,2H); 2.49 (m, 8H); 1.77 (m, 6H).

This amine was used in place of3-methoxy-4-(3-pyrrolidin-1-yl-propyl)-phenylamine in using theprocedure of Example A4 to give2-[3-methoxy-4-(3-pyrrolidin-1-yl-propyl)-phenyl]-5-phenoxy-isoindole-1,3-dione.

EXAMPLE G24-(1,3-Dioxo-5-phenoxy-1,3-dihydro-isoindol-2-yl)-2-methoxymethoxy-N-(2-pyrrolidin-1-yl-ethyl)-benzamide

A solution of 2-chloro-4-nitrophenol [Specs] (345 mg, 2 mmol) in DMF (5ml) was treated with sodium hydride (60% oil dispersion, 140 mg, 3.5mmol), then chloromethylmethyl ether (193 mg, 182 ul, 2.4 mmol). Themixture was stirred for 24 h then methanol (5 ml) added, the mixturestirred for a further 1 h then evaporated, the residue dissolved indichloromethane, filtered, evaporated and the residue purified by flashchromatography (diethyl ether-hexane) to afford1-chloro-2-methoxymethoxy-4-nitro-benzene as a clear oil;

¹H NMR (CDCl₃): δ 3.55 (3H, s), 5.35 (2H, s), 7.53 (1H, d), 7.84 (1H,dd), 8.05 (1H, d).

This material (445 mg, 2.05 mmol) was dissolved in DMF (5 ml) andtreated with N-2-hydroxyethylpyrrolidine (288 mg, 2.5 mmol), and sodiumhydride (60% oil dispersion, 90 mg, 2.3 mmol), added. The mixture washeated to 80° C. for 8 hours then cooled and stirred at RT for 30 h. Thesolvent was removed in vacuo, and the residue subjected to flashchromatography (aq. ammonia-methanol-dichloromethane) to afford1-[2-(2-methoxymethoxy-4-nitro-phenoxy)-ethyl]-pyrrolidine as a waxysolid (449 mg, 1.5 mmol).

¹H NMR (CDCl₃): δ 1.81 (4H, m), 2.66 (4H, m), 2.97 (2H, t), 3.53 (3H,s), 4.25 (2H, t), 5.26 (2H, s), 6.95 (1H, d), 7.94 (1H, dd), 8.00 (1H,d).

This material (449 mg, 1.5 mmol) was dissolved in ethanol (30 ml) andhydrogenated on 10% Pd on carbon (100 mg) for 6 hours at RTP. Thecatalyst was removed by filtration and the filtrate evaporated to give3-methoxymethoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine as a whitesolid;

¹H NMR (CDCl₃): δ 1.80 (4H, m), 2.64 (4H, m), 2.86 (2H, t), 3.4 (2H,brs), 3.50 (3H, s), 4.07 (2H, t), 5.16 (2H, s), 6.28 (1H, dd), 6.54 (1H,d), 6.76 (1H, d)

This material was treated with 3-phenoxyphthalic anhydride in the samemanner as for 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine inExample A4 to give the title compound, which crystallised from diluteTFA in ether as a trifluoroacetate salt.

EXAMPLE G32-[3-(2-Methoxy-ethoxy)-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-phenoxy-isoindole-1,3-dione

2-Chloro-4-nitrophenol was treated with 2-methoxyethyl chloride[Aldrich] in place of chloromethyl methyl ether in the procedure ofExample G2 to give the title compound, which crystallised from diluteTFA in ether as a trifluoroacetate salt.

EXAMPLE G42-[3-Methoxymethyl-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-phenoxy-isoindole-1,3-dione

1-Chloro-2-methoxymethyl-4-nitro-benzene [Patent: US 5084449 A] wasutilised in place of 1-chloro-2-methoxymethoxy-4-nitro-benzene in theprocedure of Example G2 to afford the title compound as a white solid asthe trifluoroacetate salt.

EXAMPLE G52-[3-Hydroxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5-phenoxy-isoindole-1,3-dione

4-(1,3-Dioxo-5-phenoxy-1,3-dihydro-isoindol-2-yl)-2-methoxymethoxy-N-(2-pyrrolidin-1-yl-ethyl)-benzamide[Example G2] was treated with trifluoroacetic acid (1 ml, 1M indichloromethane). After 30 minutes, the solvent was removed to affordthe title compound as a trifluoroacetate salt.

EXAMPLE G62-{4-[2-(2,5-Dimethyl-pyrrolidin-1-yl)-ethoxy]-3-methoxy-phenyl}-5-phenoxy-isoindole-1,3-dione

2,5-dimethyl-pyrrolidine was treated in the same manner as azetidine inExample G11 to give first

1-(2,5-dimethyl-pyrrolidin-1-yl)-2-(2-methoxy-4-nitro-phenoxy)-ethanone;¹HNMR (CDCl₃): δ_(—)7.86 (dd, 1H), 7.76 (d, 1H), 6.93 (d, 1H), 4.85 (bm,2H), 4.12 (bm, 2H), 3.96 (s, 3H), 2.11 (bm, 1H), 1.99 (bm, 1H), 1.70(bm, 2H), 1.30 (m, 6H).

This was treated in the same manner as1-azetidin-1-yl-2-(2-methoxy-4-nitro-phenoxy)-ethanone [Example 19] togive 1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-2,5-dimethyl-pyrrolidine;

¹H NMR (CDCl₃): δ 7.89 (dd, 1H), 7.74 (d, 1H), 6.92 (m, 1H), 4.16 (t,2H), 3.94 (s, 3H), 2.71 (m, 2H), 1.87 (m, 2H), 1.39 (m, 2H), 1.15 & 1.05(d, 6H).

This material was treated in the same manner as1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-azetidine in Example G11 to givethe title compound (as a mixture of meso isomers and enantiomers).

EXAMPLE G72-{4-[2-(2-methyl-pyrrolidin-1-yl)-ethoxy]-3-methoxy-phenyl}-5-phenoxy-isoindole-1,3-dione

2-methylpyrrolidine was treated in the same manner as azetidine inExample G11 to give first2-(2-methoxy-4-nitro-phenoxy)-1-(2-methyl-pyrrolidin-1-yl)-ethanone; ¹HNMR (CDCl₃): δ 7.84 (dd, 1H), 7.75 (d, 1H), 6.94 (d, 1H), 4.79 (s, 2H),4.23 (bm, 3H), 3.96 (s, 3H), 3.53 (bm, 2H), 1.96 (bm, 4H), 1.20 (d, 3H).This was treated in the same manner as1-azetidin-1-yl-2-(2-methoxy-4-nitro-phenoxy)-ethanone [Example 19] togive 1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-2-methyl-pyrrolidine;

¹H NMR (CDCl₃): δ 7.89 (dd, 1H), 7.74 (d, 1H), 6.92 (d, 1H), 4.24 (t,2H), 3.94 (s, 3H), 3.28 (m, 2H), 2.66 (q, 1H, J=6.5 Hz), 2.4 (m, 2H),1.95 (m, 1H), 1.79 (m, 2H), 1.46 (m, 1H), 1.14 (d, 3H, J=6.07 Hz). Thismaterial was treated in the same manner as1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-azetidine in Example G11 to givethe title compound.

EXAMPLE G82-{4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-3-methoxy-phenyl}-5-phenoxy-isoindole-1,3-dione

2-Methylpiperidine was treated in the same manner as azetidine inExample G11 to give first2-(2-methoxy-4-nitro-phenoxy)-1-(2-methyl-piperidin-1-yl)-ethanone; ¹HNMR (CDCl₃): δ 7.85 (dd, 1H), 7.75 (d, 1H), 6.97 (d, 1H), 4.88 (s, 2H),3.96 (s, 3H), 1.72-1.65 (bm, 6H), 1.30-1.13 (bm, 6H); m/z [AP+] 309.2(MH⁺, 100%). This was treated in the same manner as1-azetidin-1-yl-2-(2-methoxy-4-nitro-phenoxy)-ethanone [Example 19] togive 1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-2-methyl-piperidine.

¹H NMR (CDCl₃): δ 7.86 (dd, 1H), 7.76 (d, 1H), 6.93 (d, 1H), 4.91 (bm,2H), 3.96 (s, 3H), 1.85 (bm, 2H), 1.63 (bm, 4H), 1.56-1.50 (bm, 2H),1.32-1.21 (bm, 6H); m/z [AP+] 323.2 (MH⁺, 100%). This material wastreated in the same manner as1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-azetidine in Example G11 to givethe title compound.

EXAMPLE G92-{4-[2-((cis)-2,6-dimethyl-piperidin-1-yl)-ethoxy]-3-methoxy-phenyl}-5-phenoxy-isoindole-1,3-dione

2,5-(cis)-Dimethylpiperidine was treated in the same manner as azetidinein Example G11 to give first1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-(cis)-2,6-dimethyl-piperidine;¹H NMR (CDCl₃): δ 7.89 (dd, 1H), 7.74 (d, 1H), 6.94 (d, 1H), 4.21 (t,2H), 3.94 (s, 3H), 3.17 (q, 1H), 2.95 (m, 1H), 2.84 (q, 1H), 2.39 (m,2H), 1.65 (m, 4H), 1.33 (m, 2H), 1.12 (d, 3H).

This was treated in the same manner as1-azetidin-1-yl-2-(2-methoxy-4-nitro-phenoxy)-ethanone [Example 19] togive1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-(cis)-2,6-dimethyl-piperidine;

¹H NMR (CDCl₃): δ 7.89 (dd, 1H), 7.74 (d, 1H), 6.91 (d, 1H), 4.09 (t,2H), 3.93 (s, 3H), 3.11 (t, 2H), 2.56 (m, 2H), 1.69 (m, 1H), 1.55 (bm,2H), 1.32 (m, 3H), 1.18 (d, 6H). This material was treated in the samemanner as 1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-azetidine in ExampleG11 to give the title compound.

EXAMPLE G102-{4-[2-(2,2,6,6-tetramethyl-piperidin-1-yl)-ethoxy]-3-methoxy-phenyl}-5-phenoxy-isoindole-1,3-dione

2,2,6,6-Tetramethylpiperidine was treated in the same manner asazetidine in Example G11 to give first2-(2-methoxy-4-nitro-phenoxy)-1-(2,2,6,6-tetramethyl-piperidin-1-yl)-ethanone;

¹H NMR (CDCl₃): δ 7.84 (dd, 1H), 7.75 (d, 1H), 6.86 (d, 1H), 4.84 (s,2H), 3.96 (s, 3H), 1.77 (bm, 6H), 1.49 (s, 12H).

This was treated in the same manner as1-azetidin-1-yl-2-(2-methoxy-4-nitro-phenoxy)-ethanone [Example 19] togive1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-2,2,6,6-tetramethyl-piperidine;

¹H NMR (CDCl₃): δ 7.89 (dd, 1H), 7.74 (d, 1H), 6.92 (d, 1H), 3.96 (m,5H), 2.99 (t, 2H), 1.55 (bm, 2H), 1.08 (s, 12H).

This material was treated in the same manner as1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-azetidine in Example G11 to givethe title compound.

EXAMPLE G112-[4-(2-Azetidin-1-yl-ethoxy)-3-methoxy-phenyl]-5-phenoxy-isoindole-1,3-dione

A suspension of (2-methoxy-4-nitro-phenoxy)acetic acid [FEBS Lett.(1983), 153(2), 431], (3.12 g 15.9 mmol) in dichloromethane (100 ml) wascooled down to 0° C. in an ice bath before oxalyl chloride (5.26 g, 41.7mmol) was added. The reaction mixture was stirred for 45 minutes, givinga clear solution. The solvents were removed in vacuo to give(2-methoxy-4-nitro-phenoxy)-acetyl chloride as a pale yellow solid.(3.41 g, 100%);

¹H NMR (CDCl₃): δ 7.87 (dd, 1H,), 7.81 (d, 1H), 6.92 (d, 1H), 5.09 (s,2H), 3.98 (s, 3H).

A solution of this acid chloride (300 mg, 1.22 mmol) was dissolved indichloromethane (12 ml) and treated with azetidine (76 mg, 1.34 mmol)followed by triethylamine (370 mg, 3.66 mmol). The reaction mixture wasstirred at RT for 16 h under an argon atmosphere. The solvent wasremoved in vacuo to give a dark brown oil which was purified by flashchromatography on silica gel (eluting withdichloromethane-methanol-aqueous ammonia) to give1-azetidin-1-yl-2-(2-methoxy-4-nitro-phenoxy)-ethanone as a yellow oil(150 mg, 46%);

¹H NMR (CDCl₃): 7.88 (dd, 1H), 7.77 (d, 1H), 6.91 (d, 1H), 4.70 (s, 2H),4.37 (t, 2H), 4.11 (t, 2H), 3.96 (s, 3H), 2.34 (q, 2H).

This amide was dissolved in THF (15 ml) then borane (5.6 ml, 1M solutionin THF) was introduced. The reaction mixture was stirred for 18 hours at50° C. under argon. Excess borane was quenched by the dropwise additionof MeOH then aq HCl (2M, 200 ul). The solvent was removed in vacuo andthe residual oil partitioned between ethyl acetate and a saturatedsolution of aqueous sodium bicarbonate (20 ml). The aqueous phase wasextracted with ethyl acetate (3×50 ml). The combined ethyl acetatelayers were washed with brine and dried over MgSO₄. The solvent wasremoved in vacuo to yield1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-azetidine as a pale red oil (53mg, 38%);

¹H NMR (CDCl₃): 7.89 (dd, 1H, J=8.9), 7.73 (d, 1H), 6.89 (d, 1H), 4.09(t, 2H), 3.93 (s, 3H), 3.35 (t, 4H), 2.91 (t, 2H), 2.13 (t, 2H).

1-[2-(2-methoxy-4-nitro-phenoxy)-ethyl]-azetidine (53.5 mg, 0.21 mmol)was dissolved in a 1:1 mixture of THF and ethanol (7 ml) and 10%palladium on carbon paste (150 mg) introduced. The reaction mixture wasstirred under an atmosphere of hydrogen for 50 hours at RT. The catalystwas filtered off over filter-aid and the filtrate evaporated to give4-[2-azetidin-1-yl-ethoxy]-3-methoxy-phenylamine as a brown oil (47 mg,100%). This material was treated with 3-phenoxyphthalic anhydride in thesame manner as for 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylaminein Example A4 to give the title compound.

EXAMPLE G122-{4-[2-(7-Aza-bicyclo[2.2.1]hept-7-yl)-ethoxy]-3-methoxy-phenyl}-5-phenoxy-isoindole-1,3-dione

7-Aza-bicyclo[2.2.1]heptane [J. Am. Chem. Soc. (1989), 111(5), 1776-81],was treated in the same manner as azetidine in Example G11 to give thetitle compound.

EXAMPLE G132-{4-[2-(2-Aza-bicyclo[2.2.2]oct-2-yl)-ethoxy]-3-methoxy-phenyl}-5-phenoxy-isoindole-1,3-dione

2-Aza-bicyclo[2.2.2]octane [J. Am. Chem. Soc. (1989), 111(5), 1776-81],was treated in the same manner as azetidine in Example G11 to give thetitle compound.

EXAMPLE G142-{3-Methoxy-4-[2-(4-phenyl-piperidin-1-yl)-ethoxy]-phenyl}-5-phenoxy-isoindole-1,3-dione

4-Phenylpiperidine [AstaTech] was treated in the same manner asazetidine in Example G11 to give the title compound.

EXAMPLE G155-Phenoxy-2-(2-pyrrolidin-1-ylmethyl-2,3-dihydro-benzo[1,4]dioxin-6-yl)-isoindole-1,3-dione

2-Pyrrolidin-1-ylmethyl-2,3-dihydro-benzo[1,4]dioxin-6-ylamine [WO0121577 A2] was treated with 3-phenoxyphthalic anhydride in the samemanner as for 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine inExample A4 to give the title compound.

EXAMPLE G16Dimethyl-[7-(5-phenoxy-1,3-dihydro-isoindol-2-yl)-chroman-3-ylmethyl]-amine

3-Dimethylaminomethyl-chroman-7-ylamine[WO 0121577 A2] was treated with3-phenoxyphthalic anhydride in the same manner as for4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine in Example A4 togive the title compound.

EXAMPLE G175-Phenoxy-2-(6-pyrrolidin-1-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-isoindole-1,3-dione

6-Pyrrolidin-1-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine [WO0121577 A2] was treated with 3-phenoxyphthalic anhydride in the samemanner as for 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine inExample A4 to give the title compound.

EXAMPLE G185-Phenoxy-2-(3-Pyrrolidin-1-ylmethyl-2H-chromen-7-yl)-isoindole-1,3-dione

3-Pyrrolidin-1-ylmethyl-2H-chromen-7-ylamine [WO 0121577 A2] was treatedwith 3-phenoxyphthalic anhydride in the same manner as for4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine in Example A4 togive the title compound.

EXAMPLE G195-Phenoxy-2-(6-pyrrolidin-1-ylmethyl-7,8-dihydro-naphthalen-2-yl)-isoindole-1,3-dione

6-Pyrrolidin-1-ylmethyl-7,8-dihydro-naphthalen-2-ylamine [WO 0121577 A2]was treated with 3-phenoxyphthalic anhydride in the same manner as for4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine in Example A4 togive the title compound.

EXAMPLE G202-{3-Methoxy-4-[3-(4-phenyl-piperidin-1-yl)-propoxy]-phenyl}-5-phenoxy-isoindole-1,3-dione

4-Phenyl-piperidine [Aldrich] was treated in the same manner aspyrrolidine in the procedure of Example G21 to give the title compound.

EXAMPLE G212-[3-Methoxy-4-(3-pyrrolidin-1-yl-propoxy)-phenyl]-5-phenoxy-isoindole-1,3-dione

A solution of 3-bromo-1-propanol (0.685 g, 4.93 mmol), 4-nitroguaiacol(1 g, 5.91 mmol) and tributylphosphine (1.49 g, 7.36 mmol) in 20 mltetrahydrofuran was treated with 1,1′-(azodicarbonyl)dipiperidine (1.49g, mmol), added portionwise over 5 mins, and the resulting mixturestirred for 16 hrs. The solvent was removed in vacuo and the residuespartitioned between ethyl acetate (25 ml) and 0.5 M HCl (25 ml). Theorganic phase was washed with 0.5 M NaOH (4×25 ml), water (25 ml) andsaturated brine (25 ml), then dried and concentrated to a pale yellowsolid. This was purified by flash chromatography on silica gel (elutingwith ethyl acetate-hexane) to give1-(3-bromo-propoxy)-2-methoxy-4-nitro-benzene as a white solid (300 mg,21%);

¹H NMR (DMSO) δ 2.26-2.33 (m, 2H), 3.64-3.67 (t, 2H), 3.89 (s, 3H),4.21-4.24 (t, 2H), 7.20-7.23 (d, 1H), 7.74-7.75 (d, 1H), 7.88-7.91 (dd,1H).

This material (100 mg, 0.34 mmol) was treated with pyrrolidine (27 mg,0.37 mmol) and potassium carbonate (96.7 mg, 0.68 mmol) in DMF (10 ml).The mixture was heated to 70° C. for 16 hrs and the resulting solutionpartitioned between water (25 ml) and ethyl acetate (25 ml). The organicphase was extracted and washed with water (10 ml) and brine (5 ml), thendried (MgSO₄) and concentrated to yield1-[3-(2-methoxy-4-nitro-phenoxy)-propyl]-pyrrolidine as a yellow oil (90mg, 94%);

¹H-NMR (DMSO) 61.66-1.70 (m, 4H), 1.89-1.96 (m, 2H), 2.44-2.55 (m 6H),3.88(s, 3H), 4.14-4.18 (t, 2H), 7.17-7.19 (d, 1H), 7.73-7.75 (d, 1H),7.87-7.9 (dd, 2H).

This amine (90 mg, 0.32 mmol), was dissolved in ethanol (5 ml) andtreated with 10% palladium on carbon (40 mg) then the mixture stirredunder a hydrogen atmosphere for 16 hrs. The mixture was filtered througha plug of celite and the filtrate concentrated to yield3-methoxy-4-(3-pyrrolidin-1-yl-propoxy)-phenylamine as a brown oil (75mg, 93%);

¹H-NMR (DMSO) δ 1.66-1.69(m, 4H), 1.76-1.79(m, 2H), 2.44(bm, 6H),3.66(s, 3H), 3.79-3.82(t, 2H), 4,64(bs, 2H), 6.02-6.05(dd, 1H),6.24-6.25(d, 1H), 6.61-6.63(d, 1H).

This aniline was treated with 3-phenoxyphthalic anhydride in the samemanner as for 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine inExample A4 to give the title compound.

EXAMPLE G222-{3-Methoxy-4-[3-(4-methyl-piperazin-1-yl)-propoxy]-phenyl}-5-phenoxy-isoindole-1,3-dione

N-methyl-piperazine [Aldrich] was treated in the same manner aspyrrolidine in the procedure of Example G21 to give the title compound.

EXAMPLE G232-[4-(3-Azepan-1-yl-propoxy)-3-methoxy-phenyl]-5-phenoxy-isoindole-1,3-dione

Hexamethyleneamine [Aldrich] was treated in the same manner aspyrrolidine in the procedure of Example G21 to give the title compound.

EXAMPLE G242-[3-Methoxy-4-(3-morpholin-4-yl-propoxy)-phenyl]-5-phenoxy-isoindole-1,3-dione

Morpholine [Aldrich] was treated in the same manner as pyrrolidine inthe procedure of Example G21 to give the title compound.

The following tables give examples which illustrate but do not limit theinvention in any way. TABLE A Encompassing compounds of general formula(A), a subset of formula (I) where QY = a phthalimide group, R⁶ = OMeand ML is an oxyethyl group (A)

Example No.

Z R3 [M + H]+(AP+) A1

bond Ph 473 A2

CH₂ Ph 487 A3

NH Ph 488 A4

O Ph 459 A5

NH Ph 458 A6

CH₂ Ph 457 A7

S Ph 475 A8

S p-Cl—Ph 509, 511 A9

S 3-MeO—Ph 505 A10

S 4-HO—Ph 491 A11

S 4-F—Ph 493 A12

S 4-H₂N—Ph 490 A13

S 4-F₃C—Ph 543 A14

S 4-MeO—Ph 505 A15

O 4-Cl—Ph 493, 495 A16

O 4-F—Ph 477 A17

O 4-F₃C—Ph 527 A18

O 4-F-3-Cl—Ph 561, 563 A19

O 3-Fl—Ph 477 A20

O 3-Cl—Ph 493, 495 A21

O 3-^(t)BuPh 515 A22

O 3-MeO—Ph 489 A23

O 3-Me—Ph 473 A24

O 4-Me—Ph 473 A25

O 4-NC—Ph 484 A26

O 2-NC—Ph 484 A27

O 2-MeS—Ph 505 A28

O 2-Br—Ph 537, 539 A29

O 2-Cl—Ph 493, 495 A30

O 2-F—Ph 477 A31

O 2-Et—Ph 487 A32

O 2,5-diF—Ph 495 A33

O 2-F₃C—Ph 527 A34

O 2,4-diF—Ph 495 A35

O 4-F-2- MeO—Ph 507 A36

O 2-MeO—Ph 489 A37

O

463 A38

O

451 A39

O

451 A40

O

437 A41

O

449 A42

O

465 A43

O

451

TABLE B Encompassing compounds of general formula B, a subset of formula(I) where QY = a benzene ring fused onto a 5-membered heterocyclecomposed of groups J, J′ and J″ and linked via J″; R⁶ = OMe, ML is anoxyethyl group and R³ = Ph (B)

Ex- ample No.

Z J J′ J″ [M +H]⁺[AP+, 100%] B1

bond C═O CH₂ N 459 B2

bond CH₂ C═O N 459 B3

O C═O CH₂ N 445

TABLE C Encompassing compounds of general formula (C), a subset offormula (I) where QY = a benzene ring fused onto a 6-memberedheterocycle composed of groups J, J′, J″and J′′′ and linked via J′′′ ;ML is anoxyethyl group and NR¹R² form a pyrrolidine ring. (C)

[M + H]⁺ Example [AP+, No. R³ Z J J′ J″ J′′′ 100%] C1 Ph O C═O N═ ═N— N459 C2 Ph O C═O N═ ═CH— N 458 C3 Ph O C═O NH— C═O N 474 C4 Ph O C═O N══CMe— N 472 CS Ph bond C═O N═ ═N— N 443 C6 Ph bond C═O N═ ═CH— N 442 C7Ph bond C═O NH— C═O N 458 C8 Ph bond C═O —N═ ═CMe— N 456 C9 Allyl O C═ON═ ═CH— N 422

TABLE D Encompassing compounds of general formula (D), a subset offormula (I) where QY = a benzene ring fused onto a 6-memberedheterocycle composed of groups J, J′, J″ and J′′′ and linked via J′′′ ;ML is an oxyethyl group, R⁶ = OMe (D)

Example No.

R³ Z J J′ J″ J′′′ [M + H]⁺[AP+] D1

Ph O C═O N═ ═N— N 459 D2

Ph O C═O N═ CH N 458 D3

Ph O C═O NH— C═O N 474 D4

Ph O C═O N═ ═CMe— N 472 D5

4-ClPh bond C═O N═ ═CH— N 476, 478

TABLE E Encompassing compounds of general formula (E), a subset offormula (I) where QY = a thiophene ring fused onto a 6-memberedheterocycle composed of groups J, J′, J″ and J′′′ and linked via J′′′ ;ML is an oxyethyl group, R³ = Ph; R⁶ = OMe, Z = a bond (E)

Example No.

A A′ A″ A′′′ [M + H]⁺[AP+] E1

C═O N═ ═N— N 449 E2

C═O N═ ═CH— N 448

TABLE F Encompassing compounds of general formula (F), a subset offormula (I) where QY = a thiophene ring fused onto a 6-memberedheterocycle composed of groups J, J′, J″ and J′′′ and linked via J′′′ ;ML is an oxyethyl group, R³ = Ph; R⁶ = OMe; Z = a bond (F)

Example No.

J J′ J″ J′′′ [M + H]⁺[AP+] F1

C═O N═ ═CH— N 448 F2

C═O N═ ═C(SMe)— N 494 F3

C═O NH C═S N 480

TABLE G Encompassing compounds of general formula (G), a subset offormula (I) where QY = a phthalimide group and Z is O and R³ = Ph(=phenyl). (G)

Example No.

ML R²—N—R¹ [M + H]⁺AP+ G1

(CH₂)₃—

457 G2

—O—(CH₂)₂—

489 G3

—O—(CH₂)₂—

503 G4

—O—(CH₂)₂—

473 G5

—O—(CH₂)₂—

445 G6

—O—(CH₂)₂—

487 G7

—O—(CH₂)₂—

473 G8

—O—(CH₂)₂—

487 G9

—O—(CH₂)₂—

501 G10

—O—(CH₂)₂—

529 G11

—O—(CH₂)₂—

445 G12

—O—(CH₂)₂—

485 G13

—O—(CH₂)₂—

499 G14

—O—(CH₂)₂—

549 G15

457 G16

455 G17

453 G18

453 G19

451 G20

—O—(CH₂)₃—

563 G21

—O—(CH₂)₃—

473 G22

—O—(CH₂)₃—

502 G23

—O—(CH₂)₃—

501 G24

—O—(CH₂)₃—

489

Examples given show a pKi in binding to the 353 form of the 11CByreceptor of >6; the most potent examples would have a pKi in the range7.5-8, for example A5, C5, F1.

The activity of the compounds used in this invention has been assessedby competitive binding assays to 11CBy receptors, as follows:

Radioligand Binding Studies

Radioligand binding assays were carried out on well washed membranesfrom HEK293 cells stably expressing 11CBy receptors. Membranes (5-15 mgprotein) were incubated with [¹²⁵I]-Melanin Concentrating Hormone (0.22nM)(obtained from NEN) in the presence and absence of competing testcompounds for 45 min at 37° C. in a buffer (pH7.4), containing 50 mMTris and 0.2% BSA. Non-specific binding was defined using 0.1 mM MelaninConcentrating Hormone (obtained from Bachem). The test compounds wereadded at concentrations between 10M and 10 pM in 10 concentration steps.Following incubation, the reaction was stopped by filtration throughGF/B filters and washed with 4×1 ml of ice-cold 50 mM Tris buffer.Microscint 20 (Packard) was added to the filters and the radioactivitymeasured using a Packard TopCount.

Bound cpm in the presence of test compound was expressed as a fractionof the bound cpm in the absence of test compound and plotted against theconcentration of compound. From this an IC50 was determined from whichthe pKi was calculated.

The compounds described in Examples have a pKi value of greater than 6.For example, the compounds of examples A5, C5 and F1 have a pKi in therange 7.5-8.

Study of Effects of 11CBy Antagonists on Plasma Glucagon and BloodGlucose Levels

In chronically femoral artery and vein cannulated conscious CD rats, MCH@ 50 ug/kg (iv) produced 48.7% and 21% increases in plasma glucagon fromthe pre-treatment value after 5 and 15 minutes respectively.Glucagonotropic effects of MCH produced a maximum rise in blood glucoseconcentration after 15 min (101%).

Intravenous administration of the title compound from Example A4(pKi=7.7) at a level of 15 mg/kg five minutes prior to iv bolusinjection in the rat glucagon secretion model reduced the rise in plasmaglucagon to 2.7% after 15 min with no rise after 5 minutes, while bloodglucose increased by only 44% TABLE 1 Plasma glucagon (pg/ml) and bloodglucose levels (mmol/l) in conscious CD rats Groups 0 5 min 15 minPlasma glucagon Vehicle  26.3 ± 1.6 (6) 29.35 ± 3.7 (7) 25.74 ± 1.3(7)(1 ml/kg) MCH  23.6 ± 1.2(6) 35.16 ± 2.5(7) 28.67 ± 1.61(7) (50 ug/kg)Example A4 23.45 ± 1.16(7) 30.85 ± 2.01(7) 22.87 ± 0.56(5) (15 mg/kg) +MCH Blood glucose Vehicle  6.06 ± 0.11 (7)  6.14 ± 0.23 (7)  6.3 ±0.25(7) (1 ml/kg) MCH  5.87 ± 0.22 (7)  6.5 ± 0.33 (7) 11.81 ± 1.27(7)(50 ug/kg) Example A4  5.35 ± 0.23 (7)  6.46 ± 0.46(7)  7.71 ± 0.43 (7)(15 mg/kg) + MCHParenthesis = animal numbers. Example A4 given alone produced no changein either plasma glucagon and blood glucose levels. Plasma glucagondetermined by commercial RIA kit.

1. A compound of formula (I) comprising:

a salt or solvate thereof, wherein M is a group selected from the groupconsisting of O, S, C═O, NH and CH₂; L is a 2- or 3-membered alkylenechain; wherein together M-L may be optionally substituted by at leastone moiety selected from the group consisting of methyl, ethyl, hydroxyand C₁₋₃ alkoxy; R¹ and R² are each independently selected from thegroup consisting of hydrogen, C₁₋₆ straight or branched alkyl which maybe optionally substituted by phenyl, and C₃₋₆ cycloalkyl optionallysubstituted by one or more C₁₋₆ alkyl groups; each R⁶ is the same ordifferent and is independently selected from the group consisting ofhydroxy, C₁₋₂alkyl, C₁₋₃alkoxy, halo, C₂₋₃alkenyl, benzyl, and—C(R^(a))NOR^(b), wherein R^(a) and R^(b) are each independentlyselected from the group consisting of hydrogen, methyl, methoxymethyl,methoxymethoxy, and methoxyethoxy and n is 1, 2, 3, or 4; QY is abicyclic fused heterocyclic ring wherein Q and Y are each one ring ofsaid bicyclic fused heterocyclic group, wherein said Y ring containsfrom 1 to 3 nitrogens and is bound to the phenyl ring of formula (I) viaa nitrogen atom, and said Q ring is a 5- or 6-membered aryl orheterocyclic ring having a group ZR³; Z is bound to the Q ring; Z isselected from the group consisting of a direct bond, NH, NCH₃, O, S, andCH₂; and R³ is a group selected from the group consisting of aryl,alk-2-en-1-yl, cycloalkyl and cycloalk-2-en-1-yl and wherein said aryl,alk-2-en-1-yl, cycloalkyl, and cycloalk-2-en-1-yl are optionallysubstituted from 1 to 3 times with a subsituent selected from the groupconsisting of C₁₋₃ alkyl, halo, amino, alkylamino, dialkylamino,hydroxy, C₁₋₃ alkoxy, cyano, trifluoromethyl, and methylthio groups. 2.The compound of claim 1 wherein M is O or CH₂.
 3. The compound of claim2 wherein M is O.
 4. The compound of claim 1 wherein L is (CH₂)₂.
 5. Thecompound of claim 1 wherein L is linked to the phenyl ring of formula(I) via an R⁶ substituent located in the ortho position relative to thegroup M to form a bicyclic structure.
 6. The compound of claim 5 whereinsaid bicyclic structure is selected from the group consisting of1,4-benzodioxan, benzopyran, 1,2-dihydrobenzopyran,1,2,3,4-tetrahydronaphthalene, and 1,2-dihydronaphthalene.
 7. Thecompound of claim 1 wherein (i) R¹ and R² independently are a C₁₋₆alkyl.
 8. The compound of claim 7 wherein R¹ and R² independently aremethyl and isopropyl.
 9. The compound of claim 1 wherein QY is a 5,5;5,6; 6,5; or 6,6 bicyclic fused heterocyclic ring.
 10. The compound ofclaim 1 wherein QY is a group selected from isoindole-1,3-dione,2,3-dihydro-isoindole-1-one, 3-H-benzo(1,2,3)triazin-4-one,3-H-quinazolin-4-one, 1-H-quinazoline-2,4-dione,3-H-thieno[2,3-d]-1-triazine-4-one, 3-H-thieno[2,3d]pyrimidin-4-one,3-H-thieno[3,2-d]pyrimidin-4-one,2-thioxo-2,3-dihydro-1-H-thieno[3,2-d]pyrimidine-4-one,2-methylthio-3H-thieno[3,2-d]pyrimidin-4-one.
 11. The compound of claim1 wherein at least one R⁶ is in the ortho position with respect to thegroup M.
 12. The compound of claim 1 wherein R⁶ is methoxy.
 13. Thecompound of claim 1 wherein Z is a bond or an oxygen atom.
 14. Thecompound of claim 1 wherein R³ is selected from the group consisting of(i) phenyl which is optionally substituted by halogen, hydroxy, C₁₋₃alkoxy, C₁₋₄ alkyl, cyano or trifluoromethyl, (ii) C₅₋₇ cycloakyl, (iii)C₅₋₇ 2-cycloakenyl, and (iv) C₃₋₆ alk-2-en-1-yl.
 15. The compound ofclaim 1 wherein R³ represents phenyl.
 16. A pharmaceutical compositioncomprising a compound of claim 1 or a physiologically acceptable salt orsolvate thereof and one or more pharmaceutically acceptable carriers orexcipients.
 17. A method of treating one or more Disorders whichcomprises administering to a mammal suffering from one or more of theDisorders an effective amount of a compound of claim 1 or aphysiologically acceptable salt or solvate thereof, wherein saidDisorders are selected from the group consisting of obesity, diabetes,depression, schizophrenia, sleep disorder, and anxiety.
 18. The methodof claim 17 wherein said mammal is a human.